U.S. patent application number 16/756588 was filed with the patent office on 2020-07-30 for functional biomarkers for statin therapy in age-related macular degeneration (amd).
The applicant listed for this patent is APELIOTUS TECHNOLOGIES, INC. MASSACHUSETTS EYE AND EAR INFIRMARY. Invention is credited to John G. EDWARDS, Joan W. MILLER, Demetrios VAVVAS.
Application Number | 20200243170 16/756588 |
Document ID | 20200243170 / US20200243170 |
Family ID | 66174653 |
Filed Date | 2020-07-30 |
Patent Application | download [pdf] |
![](/patent/app/20200243170/US20200243170A1-20200730-C00001.png)
![](/patent/app/20200243170/US20200243170A1-20200730-D00000.png)
![](/patent/app/20200243170/US20200243170A1-20200730-D00001.png)
![](/patent/app/20200243170/US20200243170A1-20200730-D00002.png)
![](/patent/app/20200243170/US20200243170A1-20200730-D00003.png)
![](/patent/app/20200243170/US20200243170A1-20200730-D00004.png)
![](/patent/app/20200243170/US20200243170A1-20200730-D00005.png)
![](/patent/app/20200243170/US20200243170A1-20200730-D00006.png)
![](/patent/app/20200243170/US20200243170A1-20200730-D00007.png)
![](/patent/app/20200243170/US20200243170A1-20200730-D00008.png)
![](/patent/app/20200243170/US20200243170A1-20200730-D00009.png)
View All Diagrams
United States Patent
Application |
20200243170 |
Kind Code |
A1 |
EDWARDS; John G. ; et
al. |
July 30, 2020 |
FUNCTIONAL BIOMARKERS FOR STATIN THERAPY IN AGE-RELATED MACULAR
DEGENERATION (AMD)
Abstract
Methods of using visual functions such as dark adaptation, low
luminance visual acuity, low luminance deficit, contrast
sensitivity and scotopic sensitivity as functional biomarkers for
statin therapy in AMD. These biomarkers can be used, for example,
to support clinical trials of statin therapy for AMD by identifying
participants more likely to respond, by providing an early
indication of response, or by serving as an endpoint; or to support
treatment of AMD patients with statins by identifying patients more
likely to respond, by providing an early indication of responders
vs. non-responders, or by confirming a treatment benefit.
Inventors: |
EDWARDS; John G.;
(Philadelphia, PA) ; MILLER; Joan W.; (Winchester,
MA) ; VAVVAS; Demetrios; (Boston, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
APELIOTUS TECHNOLOGIES, INC.
MASSACHUSETTS EYE AND EAR INFIRMARY |
Philadelphia
Boston |
PA
MA |
US
US |
|
|
Family ID: |
66174653 |
Appl. No.: |
16/756588 |
Filed: |
October 17, 2018 |
PCT Filed: |
October 17, 2018 |
PCT NO: |
PCT/US2018/056372 |
371 Date: |
April 16, 2020 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62573293 |
Oct 17, 2017 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 38/00 20130101;
A61K 9/00 20130101; A61K 31/40 20130101; G16H 10/20 20180101; A61B
5/4848 20130101; A61B 3/063 20130101; A61K 31/22 20130101; A61B
3/102 20130101; A61B 3/00 20130101 |
International
Class: |
G16H 10/20 20060101
G16H010/20; A61K 31/40 20060101 A61K031/40; A61B 3/10 20060101
A61B003/10; A61B 3/06 20060101 A61B003/06; A61B 5/00 20060101
A61B005/00 |
Claims
1. A method for evaluating a response of a plurality of subjects in
a clinical trial of a statin therapy for treatment of AMD, the
method comprising the steps of: a. optionally identifying the
plurality of subjects or having the plurality of subjects
identified as having AMD; b. administering or having administered
the statin therapy to the plurality of subjects; c. measuring or
having measured one or more functional biomarkers in the plurality
of subjects; d. determining or having determined a baseline value
for each of the plurality of subjects from the one or more
measurements of step c; e. measuring or having measured the one or
more functional biomarkers in the plurality of subjects at one or
more second or later time points; f. determining or having
determined a corresponding subsequent value for each of the
plurality of subjects from the one or more measurements of step e;
and g. using as a clinical trial endpoint a comparison of the
subsequent value to the baseline value or an earlier subsequent
value; and h. optionally taking an action based on the clinical
trial endpoint.
2. The method of claim 1, wherein measuring the one or more
functional biomarkers comprises measuring one or more of dark
adaptation, low luminance visual acuity, low luminance deficit,
contrast sensitivity, or scotopic sensitivity.
3. The method of claim 1, wherein the functional biomarker is dark
adaptation.
4. The method of claim 3, wherein the baseline value and subsequent
value are a rod intercept time.
5. The method of claim 4, wherein the rod intercept time is
determined using a dark adaptometer under the following conditions:
a. a 70% effective bleach and a 5.degree. or 12.degree.
eccentricity test location; b. a 76% effective bleach and a
5.degree. or 12.degree. eccentricity test location; c. a 70%
effective bleach and a 5.degree. eccentricity test location; d. a
70% effective bleach and a 12.degree. eccentricity test location;
e. a 76% effective bleach and a 5.degree. eccentricity test
location; or f. a 76% effective bleach and a 12.degree.
eccentricity test location.
6. The method of claim 5, wherein the 5.degree. or 12.degree.
eccentricity test location are centered on the inferior visual
meridian.
7. The method of claim 5, wherein a rod intercept criterion
sensitivity level is from 5.times.10.sup.-2 scotopic cd/m.sup.2 to
5.times.10.sup.-4 scotopic cd/m.sup.2 or is 5.times.10.sup.-3
scotopic cd/m.sup.2.
8. The method of claim 1, wherein the statin therapy is
atorvastatin at a dose from 40 mg to 120 mg daily.
9. The method of claim 1, wherein the statin therapy is
cerivastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin,
or simvastatin at a dose from 40 mg dose equivalent to atorvastatin
to 120 mg dose equivalent to atorvastatin daily.
10. The method of claim 1, wherein the clinical trial endpoint is a
primary or registration endpoint or a secondary or exploratory
endpoint.
11. The method of claim 1, wherein the clinical trial endpoint is
used to provide an early indication of efficacy at an interim
period during the clinical trial.
12. The method of claim 1, wherein the action is a. determining or
having determined an early indication of efficacy at an interim
period during the clinical trial; b. making or having made a
decision on continuing the clinical trial; c. terminating or having
terminated the clinical trial; d. adding or having added additional
subjects to the clinical trial; e. changing or having changed a
parameter of the clinical trial; or f. a combination of the
foregoing.
13. A method for stratifying a plurality of subjects who have AMD
and are participating in or may participate in a clinical trial of
a statin therapy for treatment of AMD, the method comprising the
steps of: a. measuring or having measured one or more functional
biomarkers in each of the plurality of subjects; b. determining or
having determined a subject value for each of the plurality of
subjects from the one or more measurements of step a to provide a
subject value for each of the plurality subjects; and c.
stratifying the plurality of subjects based on the subject
values.
14-23. (canceled)
24. A method for identifying an early indication of a response to a
statin therapy in a subject in a clinical trial of the statin
therapy for treatment of AMD, the method comprising the steps of:
a. optionally identifying the subject or having the subject
identified as having AMD; b. administering or having administered
the statin therapy to the subject; c. measuring or having measured
one or more functional biomarkers in the subject; d. determining or
having determined a baseline value for the subject from the one or
more measurements of step c; e. measuring or having measured the
one or more functional biomarkers in the subject at one or more
later time points; f. determining or having determined a
corresponding subsequent value from the one or more measurements of
step e; and g. identifying the early indication of a response to
the statin therapy in the subject if a comparison of the subsequent
value to the baseline value or an earlier subsequent value
satisfies an early indication criteria.
25-33. (canceled)
34. A method for selecting or identifying a subject for
participation in or exclusion from a clinical trial of a statin
therapy for treatment of AMD, the method comprising the steps of:
a. optionally identifying the subject or having the subject
identified as having AMD; b. measuring or having measured one or
more functional biomarkers in the subject; c. determining or having
determined a subject value for the subject from the one or more
measurements of step b; d. comparing the subject value to a
corresponding reference range; and e. selecting or identifying the
subject for participation if the subject value is within the
corresponding reference range, or selecting or identifying the
subject for exclusion if the subject value is outside the
corresponding reference range.
35-44. (canceled)
45. A method for treating a subject suffering from AMD with a
statin, the method comprising the steps of: a. measuring or having
measured one or more functional biomarkers in the subject; b.
determining or having determined a baseline value for the subject
from the one or more measurements of step a; c. administering or
continuing to administer a statin treatment to the subject at an
initial statin dose; d. measuring or having measured the one or
more functional biomarkers in the subject at one or more later time
points; e. determining or having determined a subsequent value for
the subject from the one or more measurements of step d; and f.
making a treatment decision based on the subsequent value and the
baseline value or the subsequent value and an earlier subsequent
value, wherein the treatment decision is: i. continuing the statin
treatment without change; ii. continuing the statin treatment with
an increase in the dose of the statin being administered as
compared to the initial dose or decrease in the dose of the statin
being administered as compared to the initial dose; iii. continuing
statin treatment therapy with a different statin either at the same
equivalent dose as compared to the initial dose, a higher
equivalent dose as compared to the initial dose, or a lower
equivalent dose as compared to the initial dose; or iv.
discontinuing the statin treatment.
46-58. (canceled)
59. A method of selecting a subject suffering from AMD for
treatment with a statin therapy, the method comprising the steps
of: a. measuring or having measured one or more functional
biomarkers in the subject; b. determining or having determined a
subject value for the subject from the one or more measurements of
step a; c. comparing the subject value to a corresponding reference
range; and d. selecting the subject for treatment with the statin
therapy if the subject value falls within the reference range or
not selecting the subject for treatment with the statin therapy if
the subject value falls outside the reference range.
60-69. (canceled)
70. The method of claim 11, wherein the early indication of
efficacy is established if the comparison of the subsequent value
to the baseline value or an earlier subsequent value satisfies an
early indication criteria.
71. The method of claim 70, wherein the early indication criteria
is: a. no change in the subsequent value as compared to the
baseline value or an earlier subsequent value; b. an improvement in
the subsequent value as compared to the baseline value or an
earlier subsequent value; or c. a worsening of less than 10% in the
subsequent value as compared to the baseline value or an earlier
subsequent value.
72. The method of claim 70, wherein the baseline value, the
subsequent value and the earlier subsequent value are each a rod
intercept time.
73. The method of claim 72, wherein the early indication criteria
is: a. no change in the subsequent value as compared to the
baseline value or an earlier subsequent value; b. an improvement in
the subsequent value as compared to the baseline value or an
earlier subsequent value; or c. a worsening of less than 180
seconds in the subsequent value as compared to the baseline value
or an earlier subsequent value.
Description
TECHNICAL FIELD
[0001] Described herein are methods of using visual functions such
as dark adaptation, low luminance visual acuity, low luminance
deficit, contrast sensitivity, and scotopic sensitivity as
functional biomarkers for statin therapy in AMD. These biomarkers
can be used, for example, to support clinical trials of statin
therapy for AMD by identifying participants more likely to respond,
by providing an early indication of response, or by serving as an
endpoint; or to support treatment of AMD patients with statins by
identifying patients more likely to respond, by providing an early
indication of responders vs. non-responders, or by confirming a
treatment benefit.
BACKGROUND
[0002] Age-related macular degeneration (AMD) is a multifactorial
heterogeneous disease, with at least 100 different at-risk genes
reported in the literature and with several different phenotypes,
including types and size of drusen (Miller, 2013 Am J Ophthalmol
155(1):1-35.e13). AMD is the leading cause of irreversible vision
loss in adults in the Western world (Wong et al., 2014 Lancet Glob
Health 2(2):e106-16).
[0003] AMD is broadly classified into two types. The atrophic or
"dry" form is the most prevalent, characterized by accumulation of
extracellular deposits, termed drusen, between the retinal
pigmented epithelium (RPE) and the choroid. Progression to advanced
AMD may involve, for example, atrophy of the RPE and/or one or more
photoreceptors, and/or abnormal choroidal neovascularization
(neovascular or "wet" AMD). Though it is less prevalent than the
dry form, neovascular AMD is associated with rapid vision loss.
However, despite effective antiangiogenic treatments for
neovascular AMD, effective treatments are lacking for the more
prevalent dry form.
[0004] One of the hallmark manifestations of AMD is the
accumulation of drusen, the components of which are derived from
local tissues (RPE/retina) and from the circulation (Curcio et al.,
2011 Br J Ophthalmol 95(12):1638-45; Wu et al., 2010 J Neurochem
114(6):1734-44). Also associated with AMD are drusenoid pigment
epithelial detachments (PEDs), in which the retinal pigment
epithelium separates from the underlying Bruch's membrane due to
the presence of one or more drusen. Drusen can be hard drusen or
soft drusen. "Hard" drusen are small, distinct and far away from
one another, and may not cause vision problems for a long time, if
at all. "Soft" drusen have poorly defined edges, are large, and
cluster closer together. Lipids are a major constituent of drusen,
with esterified cholesterol (EC), unesterified cholesterol (UC),
and phosphatidyl choline constituting 40% of the volume of hard
drusen. Soft drusen are more fragile than hard drusen and oily upon
dissection, consistent with high lipid constitution. The presence
of soft drusen is one of the major risk factors for the subsequent
development of advanced dry or wet AMD.
SUMMARY
[0005] To make clinical trials and other studies of statin therapy
for AMD more practical and affordable and to reduce risk in
treatment of AMD patients using statin therapy, there is a need for
biomarkers that are more sensitive to AMD pathology, and in
particular functional biomarkers linked to the mechanism of action
for statin therapy. As disclosed herein, visual functions such as
dark adaptation, low luminance visual acuity, low luminance
deficit, contrast sensitivity, and scotopic sensitivity can be used
as functional biomarkers in AMD. These biomarkers can be used, for
example to support clinical trials of statin therapy for AMD by
identifying participants more likely to respond, by providing an
early indication of response, or by serving as an endpoint; or to
support treatment of AMD patients with statins by identifying
patients more likely to respond, by providing an early indication
of responders vs. non-responders, or by confirming/demonstrating a
treatment benefit.
[0006] Described herein are methods that include measuring one or
more functional biomarkers in a subject who has age-related macular
degeneration (AMD) to provide a baseline value (i.e., a value based
on or derived from the one or more functional biomarker
measurements); administering a treatment comprising a statin to the
subject; measuring the one or more functional biomarkers to provide
a corresponding subsequent value (i.e., a value determined in the
same fashion as the baseline value from the one or more functional
biomarker measurements) at a second or later time point; and
optionally comparing the baseline value to the corresponding
subsequent value.
[0007] Also described herein are methods for determining or
predicting efficacy of a treatment for AMD in a subject, wherein
the treatment comprises administration of a statin.
[0008] In certain embodiments, such treatment for AMD may have as
the objective preventing or delaying progression of AMD in a
subject (for example, to prevent or delay atrophy of the RPE, to
prevent or delay atrophy of one or more photoreceptors, to prevent
or delay vision loss, and/or to prevent or delay progression from
early AMD to advanced AMD). In certain embodiments, such treatment
for AMD may have as the objective regression of AMD in a subject
(for example, regression of drusen, regression of PEDs, and/or
improvement in visual acuity). The methods include identifying the
subject as having AMD; measuring one or more functional biomarkers
in the subject to provide a baseline value; administering a statin
treatment to the subject; measuring the one or more functional
biomarkers to provide a corresponding subsequent value at a second
or later time point; and optionally comparing the baseline value to
the corresponding subsequent value. In some embodiments, an
improvement or no change from the baseline value indicates that the
treatment is effective or likely to be effective for treatment of
AMD in the subject. For example, when the goal of the treatment is
stopping or slowing progression of AMD in the subject, no change
from the baseline value indicates that the treatment is effective
or likely to be effective. In some embodiments, a worsening or no
change from the baseline value indicates that the treatment is
ineffective or likely to be ineffective for treatment of AMD in the
subject. For example, when the goal of the treatment is regression
of AMD in the subject, no change from the baseline value indicates
that the treatment is ineffective or likely to be ineffective.
[0009] In some embodiments, measuring one or more functional
biomarkers comprises measuring one or more of dark adaptation, low
luminance visual acuity, low luminance deficit, contrast
sensitivity, or scotopic sensitivity.
[0010] In some embodiments, the second or later time point is one
or more of about 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 24, and/or 36
weeks; 30, 60, 90, 180, 270 and/or 365 days; or 1, 2, 3, and/or 4
quarters after initiation of the treatment. In some embodiments,
the second or later time point is one or more of about 1, 2, 3, 4,
5, 6, 8, 9, 10, 11, 12, 24, and/or 36 weeks; 30, 60, 90, 180, 270
and/or 365 days; or 1, 2, 3, and/or 4 quarters after the baseline
value is determined.
[0011] In some embodiments, the subject is a candidate being
screened for a clinical trial, or a participant in a clinical
trial. In some embodiments, the subject is not in a clinical trial.
In some embodiments, the subject is a patient being managed by a
physician outside of a clinical trial.
[0012] In some embodiments, the comparison of the baseline value to
the corresponding subsequent value is used as a primary or
registration endpoint to determine success or failure of a clinical
trial, as a secondary endpoint in a clinical trial, or as an
exploratory endpoint in a clinical trial, wherein the clinical
trial involves the administration of a statin to subjects with
AMD.
[0013] Also provided herein are methods for selecting a therapy for
a subject who has AMD (or selecting a subject for a therapy). The
methods include identifying a subject as having AMD; measuring one
or more functional biomarkers in the subject to determine a subject
value (i.e., a value based on or derived from the one or more
functional biomarker measurements); and comparing the subject value
to a corresponding reference range (i.e., a reference range for the
subject value). The methods can also optionally include identifying
the subject as having a subject value within the reference range
and selecting a therapy comprising statin administration for the
subject, or identifying the subject as having a subject value
outside the reference range and selecting a therapy not comprising
statin administration for the subject.
[0014] In some embodiments, the presence of a subject value within
the reference range indicates that the subject is suitable for
treatment with a statin therapy.
[0015] In some embodiments, the methods include administering a
therapy comprising statin administration to the subject who has a
subject value within the reference range.
[0016] Also provided herein are methods for selecting or
identifying subjects for participation in or exclusion from a
clinical trial of a statin therapy for AMD. The methods include
optionally identifying the subject as having AMD; measuring one or
more functional biomarkers in the subject to provide a subject
value; comparing the subject value to a corresponding reference
range; and identifying the subject as having a subject value within
the corresponding reference range and being appropriate for
inclusion in the trial, or identifying the subject as having a
subject value outside the corresponding reference range and being
appropriate for exclusion from the trial.
[0017] In some embodiments, the methods include including a subject
in the clinical trial who is identified as being appropriate for
inclusion. In some embodiments, the methods include excluding a
subject from the clinical trial who is identified as being
appropriate for exclusion.
[0018] Also provided herein are methods for stratifying subjects
who have AMD and are participating in a clinical trial of a statin
therapy for AMD. The methods include measuring one or more
functional biomarkers in the subject to provide a subject value for
each subject; and stratifying the subjects based on the subject
values.
[0019] In some embodiments of the methods described herein,
measuring one or more functional biomarkers comprises measuring one
or more of dark adaptation, low luminance visual acuity, low
luminance deficit, contrast sensitivity, or scotopic
sensitivity.
[0020] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Methods
and materials are described herein for use in the present
invention; other, suitable methods and materials known in the art
can also be used. When a specific method is referenced for
accomplishing a specific task or result, the specific method will
not be replaceable by other methods known in the art unless stated
otherwise herein. The materials, methods, and examples are
illustrative only and not intended to be limiting. All
publications, patent applications, patents, sequences, database
entries, and other references mentioned herein are incorporated by
reference in their entirety unless otherwise indicated. In case of
conflict between information incorporated by reference and the
present specification, the present specification, including
definitions, will control.
[0021] Other features and advantages of the invention will be
apparent from the following detailed description and figures, and
from the claims.
DESCRIPTION OF DRAWINGS
[0022] FIG. 1 illustrates the process of drusen formation (adapted
from Miller, 2016 Invest Ophthalmol Vis Sci. 57:6911-6918).
[0023] FIG. 2 illustrates the rhodopsin visual cycle.
[0024] FIG. 3A shows representative fundus photography for patient
2 (OD) (test date 8-11-15).
[0025] FIG. 3B shows representative OCT retinal imaging for patient
2 (OD) (test date 8-11-15).
[0026] FIG. 3C shows the average thickness (in .mu.M) and average
volume (mm.sup.3) of the retina as derived from the OCT imaging of
FIG. 3B.
[0027] FIG. 3D shows representative fundus photography for patient
2 (OD) (test date 12-22-15).
[0028] FIG. 3E shows representative OCT retinal imaging for patient
2 (OD) (test date 12-22-15).
[0029] FIG. 3F shows the average thickness (in .mu.M) and average
volume (mm.sup.3) of the retina as derived from the OCT imaging of
FIG. 3E.
[0030] FIG. 3G shows the average change in average thickness (in
.mu.M) and average volume (mm.sup.3) of the retina as derived from
the data in FIG. 3C and 3F.
[0031] FIG. 3H shows representative fundus photography for patient
2 (OS) (test date 2-12-16).
[0032] FIG. 3I shows representative OCT retinal imaging for patient
2 (OS) (test date 2-12-16).
[0033] FIG. 3J shows the average thickness (in .mu.M) and average
volume (mm.sup.3) of the retina as derived from the OCT imaging of
FIG. 31.
[0034] FIG. 3K shows representative fundus photography for patient
2 (OS) (test date 8-5-16).
[0035] FIG. 3L shows representative OCT retinal imaging for patient
2 (OS) (test date 8-5-16).
[0036] FIG. 3M shows the average thickness (in .mu.M) and average
volume (mm.sup.3) of the retina as derived from the OCT imaging of
FIG. 3L.
[0037] FIG. 3N shows the average change in average thickness (in
.mu.M) and average volume (mm.sup.3) of the retina as derived from
the data in FIG. 3J and 3M.
[0038] FIG. 4A shows dark adaptation results for patient 2 (OD).
The date of the test was 1-26-15 and the patient was 68 years of
age on the test date. Pupil size was 7.00 mm. A spherical
correction of +4.0 and a cylindrical correction of
-1.0.times.111.degree. was used. The RI time was determined to be
18.72 min.
[0039] FIG. 4B shows dark adaptation results for patient 2 (OS).
The details are the same as in FIG. 4A, with the exception a
cylindrical correction of +1.0.times.84.degree. was used. The RI
time was determined to be 9.88 min.
[0040] FIG. 4C shows dark adaptation results for patient 2 (OD).
The date of the test was 7-30-18 and the patient was 72 years of
age on the test date. Pupil size was 4.50 mm. A spherical
correction of +3.0 was used. The RI time was determined to be 17.05
min.
[0041] FIG. 4D shows dark adaptation results for patient 2 (OS).
The details are the same as in FIG. 4C. The RI time was determined
to be 7.28 min.
[0042] FIG. 5A shows representative fundus photography and OCT
imaging for patient 5 (OD). The date of the test was 1-26-14.
[0043] FIG. 5B shows representative fundus photography and OCT
imaging for patient 5 (OS). The date of the test was 1-26-14.
[0044] FIG. 5C shows representative fundus photography and OCT
imaging for patient 5 (OD). The date of the test was 4-9-18.
[0045] FIG. 5D shows representative fundus photography and OCT
imaging for patient 5 (OS). The date of the test was 4-9-18.
[0046] FIG. 6A shows dark adaptation results for patient 5 (OD).
The date of the test was 10-16-15 and the patient was 72 years of
age on the test date. Pupil size was 8.00 mm. A spherical
correction of +6.0 and a cylindrical correction of
-1.0.times.68.degree. was used. The RI time was determined to be
9.68 min.
[0047] FIG. 6B shows dark adaptation results for patient 5 (OS).
The details are the same as in FIG. 6A, with the exception a
spherical correction of +7.0 and a cylindrical correction of
+1.0.times.103.degree. was used. The RI time was determined to be
11.04 min.
[0048] FIG. 6C shows dark adaptation results for patient 5 (OD).
The date of the test was 6-4-18 and the patient was 75 years of age
on the test date. Pupil size was 7.00 mm. The RI time was
determined to be 17.19 min.
[0049] FIG. 6D shows dark adaptation results for patient 5 (OS).
The details are the same as in FIG. 6C. The RI time was determined
to be 10.81 min.
DETAILED DESCRIPTION
[0050] As disclosed herein, visual functions such as dark
adaptation, low luminance visual acuity, low luminance deficit,
contrast sensitivity, and scotopic sensitivity can be used as
functional biomarkers in subjects receiving statin administration
for treatment of AMD. These functional biomarkers can be used to
support clinical trials of statin therapy for AMD, for example by
identifying participants who are more likely to respond, providing
an early indication of response, or serving as an endpoint. They
can also be used to support treatment of AMD patients using statin
therapy, for example by identifying patients more likely to
respond, providing an early indication of responders vs.
non-responders, or confirming/demonstrating a treatment
benefit.
[0051] In the present specification, the functional biomarkers
described represent aspects of visual function and can be
characterized by a variety of parameters as described herein. The
various parameters that characterize the functional biomarkers are
used herein to characterize a subject, evaluate a subject, or
evaluate a response of a subject to statin treatment/therapy for
AMD (the subject value, baseline value, and subsequent values
described herein). As an example, the functional biomarker dark
adaptation can be characterized by a parameter known as the rod
intercept time. The rod intercept time is determined from
measurements of dark adaptation and is referred to herein as a
subject value, a baseline value, and a subsequent value in the
methods described.
[0052] The disclosed functional biomarkers are impacted by several
aspects of AMD such as inflammation, oxidative stress, and impaired
retinal cell metabolism. Of particular interest, the early stages
of the AMD disease process are characterized by accumulation in the
retina of extracellular deposits of cholesterol called drusen.
Conventional drusen form between the basal lamina of the retinal
pigmented epithelium (RPE) and Bruch's membrane (BM). As
illustrated in FIG. 1, histopathologic studies have shown that
these drusen start as a thin layer spanning the macula (known as
basal linear deposits or BlinD) and progress to regions of thicker
accumulation (known as basal laminar deposits or BlamD) (Curcio et
al., 2011 Br J Ophthalmol 95:1638-1645; Miller, 2016 Invest
Ophthalmol Vis Sci 57:6911-6918). The accumulation eventually
mounds in some locations to the point where it can be detected
clinically in fundus photographs as the tip of the underlying
cholesterol iceberg. One consequence of the process of drusen
accumulation is that the cholesterol layers coating BM act as a
transport barrier between the RPE on one side of BM and the choroid
on the other side. This transport barrier impedes the supply of
oxygen and nutrients coming from the choroid to the RPE and the
removal of waste products going the opposite direction. This in
turn impacts the visual cycle, which in turn, impacts the disclosed
functional biomarkers.
[0053] The disclosed functional biomarkers are mediated at least in
part by the visual cycle. The biochemistry of the visual cycle
centers on successive photobleaching and regeneration of the
photoreceptor visual pigments (opsins) (Saari, 2012 Annu Rev Nutr
32:125-45). There are three types of photoreceptors: rods, cones
and retinal ganglion cells. FIG. 2 illustrates the biochemistry of
the rod visual pigment (rhodopsin), although the biochemistry of
the cone pigments (photopsin types I, II, and III) and the retinal
ganglion pigment (melanopsin) is thought to be very similar.
Rhodopsin consists of 11-cis-retinal and the protein opsin, and is
tightly bound in the outer segment of the rods. 11-cis-retinal is
the photoreactive portion of rhodopsin, which is converted to
all-trans-retinal when a photon of light in the active absorption
band strikes the molecule. This process goes through a sequence of
chemical reactions as 11-cis-retinal isomerizes to
all-trans-retinal. During this series of chemical steps, the nerve
fiber, which is attached to the rod photoreceptor, undergoes a
stimulus that is ultimately perceived in the brain as a visual
signal. Following the breakdown of 11-cis-retinal to
all-trans-retinal, the 11-cis-retinal is regenerated in the RPE
cells by a series of steps that result in 11-cis-retinal being
available for recombination with opsin protein. A sustaining supply
of 11-cis-retinal is derived from vitamin A coming to the RPE cells
from the choroid. The transport barrier described above (BlinD,
BlamD, and/or drusen) slows the replenishment of vitamin A,
interferes with the visual cycle, and in turn impacts the disclosed
functional biomarkers. For example, there is a marked delay in dark
adaptation even at the earliest stages of AMD, and the amount of
delay increases with disease severity (Jackson et al, 2014 Invest
Ophthalmol Vis Sci 55:1427-1431).
[0054] More recently it has been recognized that cholesterol can
also accumulate on the epical side of the RPE between the RPE and
the photoreceptor outer segments, forming what is known as
subretinal drusenoid deposits (SDDs) or reticular pseudo drusen
(Curcio et al., 2013 Retina 33(2):265-276). While the mechanism is
not yet completely understood, SDDs have an even more profound
effect than conventional drusen on the disclosed functional
biomarkers, including for example dark adaptation (Flamendorf et
al., 2015 Ophthalmology 122(10):2053-2062).
[0055] Provided herein are methods that can include the development
or use of statin therapy for treatment of AMD in a subject. As used
herein, a "subject" is a mammal, particularly a human, and includes
subjects who are in a clinical trial or applying for a clinical
trial, or whose care is being managed by a physician outside of a
clinical trial. The terms "patient" and "subject" are used
interchangeably herein. For example, the methods provided can be
used to support the development or use of statin therapy intended
to regress drusen (e.g., soft drusen), to regress PEDs, to prevent
or delay atrophy of the RPE, to prevent or delay atrophy of one or
more photoreceptors, to prevent or delay vision loss, to improve
vision (e.g., visual acuity), and/or to prevent or delay
progression from early AMD to advanced AMD (e.g., geographic
atrophy or choroidal neovascularization). In some embodiments, the
subjects have soft drusen, e.g., methods for development or use of
statin therapy in AMD subjects identified as having soft drusen. In
some embodiments, the subjects are determined after clinical
assessment to have early AMD, e.g., methods for development or use
of statin therapy in AMD subjects identified as having early AMD.
In some embodiments, the subjects are determined after clinical
assessment to have intermediate AMD, e.g., methods for development
or use of statin therapy in AMD subjects identified as having
intermediate AMD. In some embodiments, the subjects have SDDs,
e.g., methods for development or use of statin therapy in AMD
subjects identified as having SDDs. As used herein, the term
"prevent" means to reduce the risk of, and need not be 100%
prevention in all cases.
[0056] The methods can include determining a baseline value and
comparing it to a corresponding subsequent value that is determined
in the same fashion as the baseline value at a second or later time
point. The baseline and subsequent values are based on or derived
from measurement of one or more functional biomarkers in the
subject as discussed herein. In some embodiments, the baseline and
subsequent values can simply be the output associated with any one
functional biomarker measurement (e.g., the dark adaptation rod
intercept time or the number of Early Treatment Diabetic
Retinopathy Study (ETDRS) letters of low luminance deficit).
However, determination of baseline and subsequent values can also
be based on or derived from a combination of multiple functional
biomarker measurements, such as, for example, counting the number
of measurements that indicate abnormal function (e.g., dark
adaptation and low luminance deficit are measured and both
measurements fall within their respective normal range, so the
value assigned is "0", or only one falls within its normal range so
the value assigned is "1", or neither falls within its normal range
so the value assigned is "2"). Any manner of combination can be
used.
[0057] The methods can include determining a subject value and
comparing it to a corresponding reference range, wherein the
presence of a subject value within the reference range indicates,
for example, that the subject is suitable for treatment with a
statin therapy, treatable with a statin therapy, likely to respond
to a statin therapy, should continue to be treated with a statin
therapy, or should be selected for inclusion in a clinical trial
for a treatment with a statin therapy. The subject value is based
on or derived from measurement of one or more functional biomarkers
in the subject in the same manner as discussed above for baseline
and subsequent values (i.e., the subject value can simply be the
output associated with any one functional biomarker measurement, or
it can be based on or derived from any manner of combination of
multiple functional biomarker measurements). Suitable reference
ranges can be determined using methods known in the art, e.g.,
using standard clinical trial methodology and statistical analysis.
The reference range can have any relevant form. In some cases, the
reference range comprises a predetermined range that represents a
normal range for the subject value, e.g., a range for unaffected
(healthy) subjects or subjects who are not at risk of developing
AMD, or that represents an abnormal range for the subject value,
e.g., associated with subjects who have AMD.
[0058] The reference range can be, for example, a range defined by
cut-off (or threshold) values at both ends, such as the range
inside or the range outside the cut-off values for a normal
reference range, a confidence interval, a receiver operating curve,
or a stratification by disease stage or other characteristics. The
reference range can also be a range defined by a single cut-off
(threshold) value at one end (e.g., the range below the cut-off
value or the range above the cut-off value). The single cut-off
value, or "cut-point", can be, for example, a median or mean, or a
level that defines the boundary of an upper or lower quartile,
tertile, or other segment of a clinical trial population or patient
population that is determined to be statistically different from
the other segments. The reference range can be established based
upon comparative groups, such as where association with risk of
developing disease or presence of disease in one defined group is a
fold higher, or lower, (e.g., approximately 2-fold, 4-fold, 8-fold,
16-fold or more) than the risk or presence of disease in another
defined group. It can be a range, for example, where a population
of subjects (e.g., control subjects) is divided equally (or
unequally) into groups, such as a low-risk group, a medium-risk
group and a high-risk group, or into quartiles, the lowest quartile
being subjects with the lowest risk and the highest quartile being
subjects with the highest risk, or into n-quantiles (i.e., n
regularly spaced intervals) the lowest of the n-quantiles being
subjects with the lowest risk and the highest of the n-quantiles
being subjects with the highest risk. In some embodiments, the
predetermined level is a level or occurrence in the same subject,
e.g., at a different time point, e.g., an earlier time point.
[0059] Dark Adaptation
[0060] Dark adaptation is preferably measured using devices known
in the art, for example as described in U.S. Pat. No. 7,494,222.
Dark adaptation is preferably measured using modifications of the
methods known in the art, for example as described in U.S. Pat. No.
7,494,222. Briefly, the methods of the prior art as described
therein, while sitting in complete or near-complete darkness the
subject is first exposed to a bright photobleaching light to
photobleach one or more of the visual pigments. This is followed by
exposure to a series of dim stimulus lights to track visual
sensitivity recovery from the photobleach. The intensity of the
stimulus lights is gradually extinguished (generally in a staircase
fashion), and the subject indicates whether each stimulus light
presentation is detectable (e.g., by pushing a response button) or
not detectable (e.g., by failing to push the response button). The
just-detectible stimulus light intensity and the time at which it
is detected are periodically recorded to generate a dark adaptation
threshold curve. Finally, the speed of dark adaption is
characterized by a parameter extracted from the threshold curve
such as the rod intercept time or the rod-cone break time.
[0061] When referring to a dark adaptation parameter, for example,
the rod intercept time, the dark adaptation parameter may be said
to "improve," show "improvement," or "worsen," or show "worsening."
The term "improve, or show "improvement" (as well as similar terms)
means the dark adaptation parameter has changed in a beneficial
manner as would be understood by the person of ordinary skill in
the art. The term "worsen," show "worsening" (as well as similar
terms) means the dark adaptation parameter has changed in a
detrimental manner as would be understood by the person of ordinary
skill in the art. For example, the dark adaptation parameter rod
intercept time is improved when the rod intercept time decreases
(for example 15 minutes to 10 minutes), while the dark adaptation
parameter rod intercept time is worsened when the rod intercept
time increases (for example from 10 minutes to 15 minutes).
[0062] In the case of dark adaptation, important parameters are
bleach intensity and test location. The bleach intensity should be
strong enough to ensure the subject is photobleached sufficiently
to allow an accurate measurement of recovery, but not so strongly
that the recovery time is impractically long. Bleach intensities
from 10% effective bleach to 90% effective bleach are preferred.
Bleach intensities from 50% effective bleach to 80% effective
bleach are particularly preferred. Specific preferred embodiments
are a 65% effective bleach, a 70% effective bleach and a 76%
effective bleach. The test location should be selected to maximize
sensitivity for the relevant AMD population. AMD is a slow
deterioration of the macula, which occupies the central 20.degree.
of the retina. Functional impairment related to AMD progresses
radially from near the center of the macula initially toward the
periphery of the macula as the disease progresses. Test locations
from 5.degree. eccentricity (at the edge of the parafovea) to
20.degree. eccentricity (at the edge of the macula) are preferred.
Specific preferred embodiments are 5.degree. eccentricity,
8.5.degree. eccentricity and 12.degree. eccentricity. Any azimuthal
orientation can be used. A specific preferred embodiment is an
azimuthal orientation on the inferior visual meridian.
Determination of dark adaption can be based on any number of
parameters including, but not limited to, rod intercept time (i.e.,
time for recovery to a criterion visual sensitivity level),
rod-cone break time, rod recovery slope, and time to scotopic
threshold. A specific preferred embodiment is the rod intercept
time. When using the rod intercept time, criterion sensitivity
levels from 5.times.10.sup.-2 scotopic cd/m.sup.2 to
5.times.10.sup.-4 scotopic cd/m.sup.2 are preferred. A specific
preferred embodiment is 5.times.10.sup.-3 scotopic cd/m.sup.2.
[0063] In one embodiment, the following conditions are used for
measuring the dark adaptation rod intercept parameter in any of the
methods described herein: use of a 70% or 76% effective bleach, a
5.degree. or 12.degree. eccentricity test location, and a rod
intercept criterion sensitivity level of 5.times.10.sup.-3 scotopic
cd/m.sup.2.
[0064] In another embodiment, the following conditions are used for
measuring the dark adaptation rod intercept parameter in any of the
methods described herein: use of a 76% effective bleach, a
5.degree. or 12.degree. eccentricity test location, and a rod
intercept criterion sensitivity level of 5.times.10.sup.-3 scotopic
cd/m.sup.2.
[0065] In another embodiment, the following conditions are used for
measuring the dark adaptation rod intercept parameter in any of the
methods described herein: use of a 76% effective bleach, a
5.degree. eccentricity test location centered on the inferior
visual meridian, and a rod intercept criterion sensitivity level of
5.times.10.sup.-3 scotopic cd/m.sup.2.
[0066] In another embodiment, the following conditions are used for
measuring the dark adaptation rod intercept parameter in any of the
methods described herein: use of a 76% effective bleach, a
12.degree. eccentricity test location centered on the inferior
visual meridian, and a rod intercept criterion sensitivity level of
5.times.10.sup.-3 scotopic cd/m.sup.2.
[0067] Depending on the test parameters used and the subject's
health status, dark adaptation times can vary from under 2 minutes
to over 60 minutes. For example, using a 76% bleaching intensity, a
5.degree. eccentricity test location, and a rod intercept criterion
sensitivity level of 5.times.10.sup.-3 scotopic cd/m.sup.2, the rod
intercept time for a normal, healthy subject will typically be
under 6.5 minutes and the rod intercept time for an AMD patient
will typically be over 6.5 minutes, with early AMD patients
typically being around 13 minutes, intermediate AMD patients
typically being around 17 minutes, and advanced AMD patients
typically being 20 minutes or more. The rod intercept times above
are generalizations and the rod intercept times for individual
subjects may vary (for example, a subject with intermediate AMD may
have a rod intercept time significantly less than 17 minutes). For
dark adaptation, faster is better, and a decrease in dark
adaptation time (e.g., a decrease in rod intercept time, rod-cone
break time, rod recovery slope, or time to scotopic threshold)
(e.g., by at least 1-3, 3-5 or 1-5 minutes) is an improvement in
any of the methods described herein. In certain specific
embodiments in any of the methods described herein, a decrease in
rod intercept time of 1 minute, 1-3 minutes, 3-5 minutes, or 1-5
minutes) is an improvement.
[0068] AMD status has been determined in the art using a number of
recognized grading systems, such as the Beckman AMD Classification
System, the Age-Related Eye Disease Study (AREDS) Severity Scale,
the AREDS Simplified Severity Scale, the International
Classification and Grading System for AMD, and the Wisconsin
Age-Related Maculopathy Grading System. When a determination of AMD
status is required for a subject, the determination of AMD status
is made using the Beckman AMD Classification System (Ferris et al.
Ophthalmology 2013;120:844-851).
[0069] Ad discussed herein, dark adaptation may be impacted by the
accumulation of cholesterol and other lipids in the retina, even
when such accumulation does not result in observable drusen
formation. Statins are known to impact the levels of cholesterol
and other lipids. As such, the use of dark adaptation as a
functional biomarker brings to together a possible mechanism
involved in AMD pathology and a possible mechanisms of action of
the statins. Those in the art are aware that not all drugs that
successfully treat AMD have an impact on visual functions like dark
adaptation. For example, the administration of a compound that
provides neuroprotection may improve AMD by strengthening the
photoreceptors so they are less susceptible to AMD pathology;
however, such compounds will not impact dark adaptation. Those in
the art are aware that not all drugs that impact dark adaptation
will successfully treat AMD. For example, administration of large
doses of vitamin A will improve dark adaptation without improving
AMD or lessening AMD pathology.
[0070] Low Luminance Visual Acuity/Low Luminance Deficit
[0071] Low luminance visual acuity and/or low luminance deficit are
preferably measured using methods known in the art. One option is
to use standard eye charts, for example as described in Sunness et
al., 2008 Ophthalmology 115(9):1480-1488. Briefly, a neutral
density filter is placed between a normally illuminated eye chart
and the subject's eye. As in measurement of normal luminance visual
acuity, the subject is asked to start at the top line of the chart
(with the largest letters) and read down as many lines or partial
lines of letters as possible. Low luminance deficit is the
difference between normal luminance visual acuity (measured with no
intervening neutral density) and low luminance visual acuity
(measured with an intervening neutral density). A variety of eye
chart types can be used including Snellen charts and ETDRS charts.
Important parameters are the eye chart luminance level and the
amount of neutral density introduced for low luminance comparisons.
Eye chart luminance levels from 70 cd/m.sup.2 to 400 cd/m.sup.2 are
preferred. Specific preferred embodiments are 85 cd/m.sup.2, 100
cd/m.sup.2, and 130 cd/m.sup.2. Neutral density filters from 1.0
log units (a factor of 10 reduction) to 3.0 log units (a factor of
1000 reduction) are preferred. A specific preferred embodiment is
2.0 log units.
[0072] Alternatively, electronic vision testers can be used to
measure low luminance visual acuity and/or low luminance deficit,
for example as described in Chandramohan et al., 2016 Retina
36(5):1021:1031. In this approach, normal and low luminance visual
acuity are measured by displaying progressively smaller letters on
an electronic screen having a high background luminance (e.g., 16
cd/m.sup.2) or a low background luminance (e.g., 5 cd/m.sup.2) for
the respective measurements, and asking the subject to read as many
letters as possible in each case. Low luminance deficit is again
defined as the difference between normal luminance visual acuity
and low luminance visual acuity.
[0073] The more letters that can be read, the better. For example,
as with normal luminance visual acuity, low luminance visual acuity
can range from less than 50 ETDRS letters (which is equivalent to
1.0 logMAR or 20/200 on the traditional US scale and considered
"legally blind") to better than 100 ETDRS letters (which is
equivalent to 0.0 logMAR or 20/20 on the traditional US scale and
considered "normal"). AMD patients can fall anywhere along this
range depending on disease severity. Intermediate AMD patients
typically have a low luminance deficit of around 10 ETDRS letters
and advanced AMD patients typically have a low luminance deficit of
20 ETDRS letters or more. A decrease in low luminance deficit
(e.g., by at least 5-10, 10-15, or 5-15 ETDRS letters) is an
improvement.
[0074] Contrast Sensitivity
[0075] Contrast sensitivity is the reciprocal of the smallest
amount of contrast (i.e., degree of blackness to whiteness) that is
required to be able to detect a target. Contrast sensitivity is
preferably measured using standard methods, as described for
example in Owsley, 2003 Ophthalmol Clin N Am 16:171-77. Tools for
measuring contrast sensitivity include, for example, Pelli-Robson
charts, Bailey-Lovie charts, Cambridge low contrast gratings, Regan
charts, FACT charts, and computerized test systems such as the
Spaeth/Richmond contrast sensitivity test. Briefly, letters or
periodic patterns (such as sine wave or square wave gratings)
having decreasing contrast are displayed on a chart or electronic
screen, and the subject is asked to read or otherwise identify as
many of these targets as possible. An important parameter is the
background luminance level. Chart luminance levels from 10
cd/m.sup.2 to 500 cd/m.sup.2 are preferred. A specific preferred
embodiment is 85 cd/m.sup.2. The contrast of the targets can be
characterized in a variety of ways. So-called Weber contrast (the
luminance of the background minus the luminance of the target
divided by the luminance of the background) is preferred for tools
involving letters. So-called Michelson contrast (the luminance of
the brightest area minus the luminance of the dimmest area divided
by the sum of the two) is preferred for tools involving periodic
patterns.
[0076] The more letters that can be read or targets that can be
identified, the better. AMD patients typically have lower contrast
sensitivity than normal subjects. For example, using a Pelli-Robson
chart, contrast sensitivity for normal subjects typically ranges
from 38 letters (equivalent to 1.9 log contrast sensitivity) to 31
letters (equivalent to 1.55 log contrast sensitivity), while
contrast sensitivity for early, intermediate and late AMD patients
is typically 27 letters (equivalent to 1.35 log contrast
sensitivity), 24 letters (equivalent to 1.2 log contrast
sensitivity), and 19 letters (equivalent to 0.95 log contrast
sensitivity), respectively. An increase in letters read or targets
identified (e.g., at least 3-5, 5-10 or 3-10 letters/targets) is an
improvement.
[0077] Scotopic Sensitivity
[0078] Scotopic sensitivity is the dimmest light detectable in
otherwise complete or near-complete darkness. Scotopic sensitivity
is preferably measured using standard methods, as described for
example in Wu et al., 2013 Invest Ophthalmol Vis Sci 54:7378-7385.
Briefly, while sitting in complete or near-complete darkness the
subject is exposed to a series of stimulus lights. The intensity of
the stimulus lights is gradually extinguished (generally in a
staircase fashion), and the subject indicates whether each stimulus
light presentation is detectable (e.g., by pushing a response
button) or not detectable (e.g., by failing to push the response
button). The just-detectible stimulus light intensity is recorded
as a scotopic sensitivity threshold. Scotopic sensitivity testing
can be performed with or without prior dark adaptation. When
testing is performed with prior dark adaptation, scotopic
sensitivity can be characterized, for example, by a single
threshold measurement or by averaging a few threshold measurements.
When testing is performed without prior dark adaptation, scotopic
sensitivity can be characterized, for example, by measuring
thresholds until there is little or no change in the threshold
value. Scotopic sensitivity measurements can be made, for example,
using a microperimeter or a dark adaptometer.
[0079] In the case of scotopic sensitivity, important parameters
are the background luminance level, the wavelength of the stimulus
light, and the test location. Testing should be performed using a
background luminance level as low as practically possible. A
specific preferred background luminance level is 1.27 cm/m.sup.2.
The stimulus light wavelength is preferably matched to the spectral
response curve of the rod photoreceptors that are primarily
responsible for scotopic (or night) vision. Red light (i.e.,
wavelengths over 550 nm) is preferred. Specific preferred
embodiments are wavelengths clustered around 627 nm and wavelengths
clustered around 670 nm. Test locations within the macula are
preferred (i.e., from 0.degree. eccentricity to 20.degree.
eccentricity). Specific preferred test locations are 0.degree.
eccentricity, 1.degree. eccentricity, 2.33.degree. eccentricity,
4.degree. eccentricity, 5.degree. eccentricity, 6.degree.
eccentricity, 8.5.degree. eccentricity, and 12.degree.
eccentricity. Any azimuthal orientation can be used. Analysis of
scotopic sensitivity can be based on measurements at a single test
location or a combination of measurements at multiple test
locations, such as, for example, by calculating the average of
scotopic sensitivity measurements for multiple test locations or by
calculating the percentage of scotopic sensitivity measurements
below a fixed criterion. The dimmer the light that can be seen in
the dark, the better. Scotopic sensitivity is typically impaired in
AMD patients vs. normal subjects. Quantification of scotopic
sensitivity depends on the test parameters used and the subject's
health status. For example, using a background luminance level of
1.27 cm/m.sup.2, a stimulus light with wavelengths clustered around
627 nm (e.g., an LED having a central wavelength of 627 nm), and
analyzing 37 central test locations ranging from 0.degree.
eccentricity to 5.degree. eccentricity, the average scotopic
sensitivity is typically reduced by 2 to 3 dB for patients having
intermediate AMD vs. normal subjects (i.e., the dimmest light that
can be seen in the dark by an intermediate AMD patient is typically
1.5 to 2 times brighter than the dimmest light that can be seen in
the dark by a normal subject). Using the same test parameters, the
percentage of locations with reduced scotopic sensitivity can be
over 40% for intermediate AMD patients. A lessening of the
reduction in average sensitivity or a lowering of the percentage of
locations with reduced sensitivity would be an improvement.
[0080] Clinical Trial Support--Stratification/Endpoints
[0081] Administration of statins can be an effective therapy for
AMD. For example, Vavvas et al. demonstrated that use of high-dose
atorvastatin resulted in the disappearance of drusen deposits that
are the structural hallmark of AMD and improvement in vision for
43% of patients treated (Vavvas et al., 2016 EBioMedicine.
5:198-203). However, additional clinical trials are needed to
secure regulatory approvals from agencies such as the US Food and
Drug Administration (FDA) and the European Medicines Agency (EMA).
Because the clinical trial endpoints traditionally used to
establish efficacy for ophthalmic indications--such as visual
acuity and disease progression--are relatively insensitive
biomarkers for AMD, clinical trials of AMD therapies generally
require large numbers of study participants or long study
durations, often making them cost prohibitive. To make clinical
trials and other studies of statin therapy for AMD more practical
and affordable, there is a need for biomarkers that are more
sensitive to AMD pathology, and in particular for functional
biomarkers linked to the mechanism of action for statin therapy.
The disclosed functional biomarkers can be used, for example, as
the basis for inclusion/exclusion criteria or clinical trial
endpoints in the development of statins as a therapy for AMD.
[0082] In some methods, one or more of the functional biomarkers
disclosed herein is measured at the initiation of a clinical trial
to provide a subject value that indicates the likelihood of a
treatment effect or a baseline value to track treatment effect. In
some embodiments, an impaired subject value at the initiation of
the clinical trial indicates the potential for treatment response;
for example, allowing the trial investigators to decide whether the
subject should be included in or excluded from the trial. During or
after administration of a statin treatment under the clinical trial
(e.g., at one or more of 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 24,
and/or 36 weeks, or 30, 60, 90, 180, 270 and/or 360 days, or 1, 2,
3, and/or 4 quarters after initiation of the treatment), the one or
more functional biomarkers disclosed herein can be measured again
to provide a subsequent value, and the subsequent value compared to
the baseline value or an earlier subsequent value. In some
embodiments, an improvement from the baseline value indicates that
the therapy is effective or likely to be effective for the subject.
In some embodiments, no change or a worsening from the baseline
value indicates that the therapy is ineffective or likely to be
ineffective. In some embodiments, for example in patients who are
expected to experience rapidly worsening disease based on natural
history, no change from the baseline value indicates that the
therapy is effective or likely to be effective for the patient.
[0083] An advantage over endpoints traditionally used in ophthalmic
clinical trials, such as visual acuity and disease progression, is
greater sensitivity to AMD pathology. This is illustrated by a
study using dark adaptation as an endpoint to evaluate the efficacy
of vitamin A supplementation in AMD patients. In that study, Owsley
et al. examined the effect of a short course of high-dose vitamin A
(preformed retinol) in older adults with normal retinal health or
AMD (Owsley et al., 2006 Invest Ophthalmol Vis Sci
47(4):1310-1318). A randomized, double-masked, placebo-controlled
experiment was conducted. Adults at least 50 years old whose fundus
photographs for the study eye fell within steps 1 through 9 (normal
retinal health through intermediate AMD) of the extended AREDS
Grading System were randomly assigned to a 30-day course of 50,000
international units of oral retinol or placebo. The study consisted
of 104 patients with 52 each in the intervention and placebo
groups. Dark adaptation (determined using the cone time constant,
cone sensitivity, rod-cone break, rod slope, and rod sensitivity)
and visual acuity were measured at baseline and 30-day follow-up.
There was no difference between the groups for either parameter at
baseline. At 30-day follow-up, the retinol intervention group had
significantly faster dark adaptation than the placebo group. In
addition, those patients having the greatest improvement in dark
adaptation reported the greatest improvement in low luminance
mobility using a standardized low luminance questionnaire. By
contrast, there continued to be no difference in visual acuity
between the groups. After an additional 30-day washout period, the
improvement in dark adaptation reversed to the baseline level. This
study also noted that the observed differences between treatment
groups were similar in the subjects with AMD and without AMD.
Similarly, it has been shown that low luminance deficit is a strong
predictor of future visual acuity loss in AMD patients with
geographic atrophy (Sunness et al., 2008 Ophthalmology
115(9):1480-1488) and is correlated with real-world vision-related
difficulties experienced by patients with intermediate AMD (Wu et
al., 2016) Br J Ophthalmol 100:395-398).
[0084] In some embodiments, the disclosed functional biomarkers can
be used as the basis for a primary or registration endpoint to
determine success or failure of the trial. In other embodiments,
these biomarkers can be used as the basis for a secondary or
exploratory endpoint to provide further elucidation of the trial
results rather than a determination of ultimate success or failure.
These biomarkers can also be used for patient selection and/or
stratification; for example, the study population in the clinical
trial can be selected and/or stratified/classified based on subject
values derived from the biomarkers. Alternatively, these biomarkers
can be used to provide an early indication of effectiveness at an
interim look during a clinical trial that is ultimately based on a
different primary endpoint not expected to show improvement as
quickly; for example, allowing the trail sponsor to decide whether
to terminate or continue the trial.
[0085] In some embodiments, when screening patients for inclusion
in a clinical trial, those with an impaired functional biomarker
(e.g., delayed dark adaptation or a larger than normal low
luminance deficit) are more likely to respond to intervention,
simply because they have deficits that can be corrected. In some
embodiments, once treatment has started, improvement in a
functional biomarker (e.g., a shortening of dark adaptation time or
a lessening of low luminance deficit) is an early indicator of
treatment efficacy and consequently indicates those more likely to
have follow-on benefits such as disappearance of drusen or
improvement in visual acuity.
[0086] Therefore, the following methods are provided in the present
disclosure.
[0087] The present disclosure provides a method for selecting or
identifying a subject for participation in or exclusion from a
clinical trial of a statin therapy for treatment of AMD.
[0088] The method comprises the steps of: 1) optionally identifying
the subject or having the subject identified as having AMD; 2)
measuring or having measured one or more functional biomarkers in
the subject; 3) determining or having determined a subject value
for the subject from the one or more measurements of step 2; 4)
comparing the subject value to a corresponding reference range; and
5) selecting or identifying the subject for participation if the
subject value is within the corresponding reference range, or
selecting or identifying the subject for exclusion if the subject
value is outside the corresponding reference range. Such a method
can further include enrolling a subject in the clinical trial who
is identified as being appropriate for inclusion, excluding a
subject from the clinical trial who is identified as being
appropriate for exclusion, or a combination of the foregoing.
[0089] The present disclosure provides a method for selecting or
identifying a subject for participation in or exclusion from a
clinical trial of a statin therapy for treatment of AMD. The method
comprises the steps of: 1) optionally identifying the subject or
having the subject identified as having AMD; 2) measuring or having
measured dark adaptation in the subject; 3) determining or having
determined the rod intercept time from the dark adaptation
measurement to provide a subject value; 4) comparing the subject
value to a corresponding reference range; and 5) selecting or
identifying the subject for participation if the subject value is
within the corresponding reference range, or selecting or
identifying the subject for exclusion if the subject value is
outside the corresponding reference range. Such a method can
further include enrolling a subject in the clinical trial who is
identified as being appropriate for inclusion, excluding a subject
from the clinical trial who is identified as being appropriate for
exclusion, or a combination of the foregoing.
[0090] The present disclosure provides a method for stratifying a
plurality of subjects who are participating in or may participate
in a clinical trial of a statin therapy for treatment of AMD. The
method comprises the steps of: 1) optionally identifying each of
the plurality of subjects or having each of the plurality of
subjects identified as having AMD; 2) measuring or having measured
one or more functional biomarkers in each of the plurality of
subjects; 3) determining or having determined a subject value for
each of the plurality of subjects from the one or more measurements
of step 2 to provide a subject value for each of the plurality
subjects; and 4) stratifying the plurality of subjects based on the
subject values.
[0091] The present disclosure provides a method for stratifying a
plurality of subject who have AMD and are participating in or may
participate in a clinical trial of a statin therapy for treatment
of AMD. The method comprises the steps of: 1) optionally
identifying each of the plurality of subjects or having each of the
plurality of subjects identified as having AMD; 2) measuring or
having measured dark adaptation in each of the plurality of
subjects; 3) determining or having determined the rod intercept
time for each of the plurality of subjects from the dark adaptation
measurement to provide a subject value for each of the plurality of
subjects; and 4) stratifying the plurality of subjects based on the
subject values.
[0092] In any of the foregoing embodiments for stratifying a
plurality of subject who have AMD and are participating in or may
participate in a clinical trial of a statin therapy for treatment
of AMD, the subject may be stratified based on AMD status (for
example, early AMD, intermediate AMD, or late AMD) in addition to
the above criteria. For example, a subject may be stratified in a
clinical trial of a statin therapy for treatment of AMD due to the
subject value (for example, rod intercept time) and type of AMD
(for example, intermediate AMD).
[0093] The present disclosure provides a method for identifying an
early indication of a response to a statin therapy in a clinical
trial of the statin therapy for treatment of AMD. The method
comprises the steps of: 1) optionally identifying the subject or
having the subject identified as having AMD; 2) administering or
having administered the statin therapy to the subject; 3) measuring
or having measured one or more functional biomarkers in the
subject; 4) determining or having determined a subject value for
the subject from the one or more measurements of step 3; 5)
comparing the subject value to a corresponding reference range; and
6) identifying an early indication of a response to the statin
therapy in the subject if the subject value is within the
corresponding reference range.
[0094] The present disclosure provides a method for identifying an
early indication of a response to a statin therapy in a clinical
trial of the statin therapy for treatment of AMD. The method
comprises the steps of: 1) optionally identifying the subject or
having the subject identified as having AMD; 2) administering or
having administered the statin therapy to the subject; 3) measuring
or having measured one or more functional biomarkers in the
subject; 4) determining or having determined a baseline value for
the subject from the one or more measurements of step 3; 5)
measuring or having measured the one or more functional biomarkers
in the subject at one or more second or later time points; 6)
determining or having determined a corresponding subsequent value
from the one or more measurements of step 5; and 7) identifying an
early indication of a response to the statin therapy in the subject
if a comparison of the subsequent value to the baseline value or an
earlier subsequent value satisfies an early indication
criteria.
[0095] The present disclosure provides a method for identifying an
early indication of a response to a statin therapy in a clinical
trial of the statin therapy for treatment of AMD. The method
comprises the steps of: 1) optionally identifying the subject or
having the subject identified as having AMD; 2) administering or
having administered the statin therapy to the subject; 3) measuring
or having measured dark adaptation in the subject; 4) determining
or having determined the rod intercept time from the dark
adaptation measurement to provide a subject value; 5) comparing the
subject value to a corresponding reference range; and 6)
identifying an early indication of a response to the statin therapy
in the subject if the subject value is within the corresponding
reference range.
[0096] The present disclosure provides a method for identifying an
early indication of a response to a statin therapy in a clinical
trial of the statin therapy for treatment of AMD. The method
comprises the steps of: 1) optionally identifying the subject or
having the subject identified as having AMD; 2) administering or
having administered the statin therapy to the subject; 3) measuring
or having measured dark adaptation in the subject; 4) determining
or having determined the rod intercept time from the dark
adaptation measurement to provide a baseline value; 5) measuring or
having measured dark adaptation in the subject at one or more
second or later time points; 6) determining or having determined
the rod intercept time from the dark adaptation measurement to
provide a subsequent value; and 7) identifying an early indication
of a response to the statin therapy in the subject if a comparison
of the subsequent value to the baseline value or an earlier
subsequent value satisfies an early indication criteria.
[0097] In any of the foregoing methods for identifying an early
indication of a response to a statin therapy in a clinical trial,
such a method can further include continuing the subject in the
clinical trial who has shown an early indication of a response to
the statin therapy. In any of the foregoing methods for identifying
an early indication of a response to the statin therapy in a
clinical trial, such a method can be used to provide an early
indication of efficacy at an interim period during the clinical
trial, wherein the efficacy of the clinical trial is ultimately
based on a different endpoint (such as the primary or registration
endpoint) not expected to show improvement as quickly, to make a
decision on continuing the clinical trial or terminating the
clinical trial, or a combination of the foregoing.
[0098] In any of the foregoing methods for identifying an early
indication of a response to a statin therapy in a clinical trial,
the early indication criteria may be: i) no change in the
subsequent value as compared to the baseline value or an earlier
subsequent value; ii) an improvement in the subsequent value as
compared to the baseline value or an earlier subsequent value; or
iii) a worsening of less than 10% in the subsequent value as
compared to the baseline value or an earlier subsequent value.
[0099] In any of the foregoing methods for identifying an early
indication of a response to a statin therapy in a clinical trial,
the early indication criteria may be: i) no change in the
subsequent value (for example, rod intercept time) as compared to
the baseline value or an earlier subsequent value; ii) an
improvement in the subsequent value (for example, rod intercept
time) as compared to the baseline value or an earlier subsequent
value; or iii) a worsening of less than 180 seconds in the
subsequent value (for example, rod intercept time) as compared to
the baseline value or an earlier subsequent value.
[0100] In any of the foregoing embodiments for selecting or
identifying a subject for participation in or exclusion from a
clinical trial of a statin therapy for treatment of AMD, the
subject may be identified or selected based on AMD status (for
example, early AMD, intermediate AMD, or late AMD) in addition to
the above criteria. For example, a subject may be identified as
being appropriate for inclusion in a clinical trial of a statin
therapy for treatment of AMD due to the subject value (for example,
rod intercept time) falling within the corresponding reference
range and due to having intermediate AMD.
[0101] The present disclosure provides a method for conducting a
clinical trial of a statin therapy for treatment of AMD in a
plurality of subjects. The method comprises the steps of: 1)
optionally identifying the plurality of subjects or having the
plurality of subjects identified as having AMD; 2) administering or
having administered the statin therapy to the plurality of
subjects; 3) measuring or having measured one or more functional
biomarkers in the plurality of subjects; 4) determining or having
determined a subject value for each of the plurality of subjects
from the one or more measurements of step 3; 5) using the subject
value as a clinical trial endpoint; and 6) optionally taking an
action based on the clinical trial endpoint.
[0102] The present disclosure provides a method for conducting a
clinical trial of a statin therapy for treatment of AMD in a
plurality of subjects. The method comprises the steps of: 1)
optionally identifying the plurality of subjects or having the
plurality of subjects identified as having AMD; 2) administering or
having administered the statin therapy to the plurality of
subjects; 3) measuring or having measured one or more functional
biomarkers in the plurality of subjects; 4) determining or having
determined a baseline value for each of the plurality of subjects
from the one or more measurements of step 3; 5) measuring or having
measured the one or more functional biomarkers in each of the
plurality of subjects at one or more second or later time points;
6) determining or having determined a corresponding subsequent
value from the one or more measurements of step 5; 7) using as a
clinical trial endpoint a comparison of the subsequent value to the
baseline value (or an earlier subsequent value); and 8) optionally
taking an action based on the clinical trial endpoint.
[0103] The present disclosure provides a method for conducting a
clinical trial of a statin therapy for treatment of AMD in a
plurality of subjects. The method comprises the steps of: 1)
optionally identifying the plurality of subjects or having the
plurality of subjects identified as having AMD; 2) administering or
having administered the statin therapy to the plurality of
subjects; 3) measuring or having measured dark adaptation in each
of the plurality of subjects; 4) determining or having determined
the rod intercept time from the dark adaptation measurement to
provide a subject value; 5) using the subject value as a clinical
trial endpoint; and 6) optionally taking an action based on the
clinical trial endpoint.
[0104] The present disclosure provides a method for conducting a
clinical trial of a statin therapy for treatment of AMD in a
plurality of subjects. The method comprises the steps of: 1)
optionally identifying the plurality of subjects or having the
plurality of subjects identified as having AMD; 2) administering or
having administered the statin therapy to the plurality of
subjects; 3) measuring or having measured dark adaptation in each
of the plurality of subjects; 4) determining or having determined
the rod intercept time from the dark adaptation measurement to
provide a baseline value; 5) measuring or having measured dark
adaptation in each of the plurality of subjects at one or more
second or later time points; 6) determining or having determined
the rod intercept time from the dark adaptation measurement to
provide a subsequent value; 7) using as a clinical trial endpoint a
comparison of the subsequent value to the baseline value (or an
earlier subsequent value); and 8) optionally taking an action based
on the clinical trial endpoint.
[0105] In any of the foregoing embodiments for conducting a
clinical trial, the endpoint may be a primary or registration
endpoint to determine success or failure of the clinical trial. In
any of the foregoing embodiments for conducting a clinical trial,
the endpoint be a secondary or exploratory endpoint to provide an
early indication of efficacy at an interim period during the
clinical trial and/or to provide further elucidation of the trial
results rather than a determination of ultimate success or
failure.
[0106] In any of the foregoing methods for conducting a clinical
trial, taking an action based on the clinical trial endpoint can
be: i) determining or having determined an early indication of
efficacy at an interim period during the clinical trial, wherein
the efficacy of the clinical trial is ultimately based on a
different endpoint (such as the primary or registration endpoint)
not expected to show improvement as quickly; ii) making or having
made a decision on continuing the clinical trial; iii) terminating
or having terminated the clinical trial; iv) adding or having added
additional subjects to the clinical trial; v) changing or having
changed a parameter of the clinical trial (for example, adding or
deleting a secondary endpoint; the dose of a statin, the type of
statin administered, or the administration frequency of the
statin); vi) or a combination of the foregoing.
[0107] In the foregoing methods for selecting or identifying a
subject, methods for stratifying a plurality of subjects, methods
for identifying an early indication, or methods for conducting a
clinical trial where a functional biomarker is measured, the
functional biomarker may be one or more of dark adaptation, low
luminance visual acuity, low luminance deficit, contrast
sensitivity, or scotopic sensitivity.
[0108] In the foregoing methods for selecting or identifying a
subject, methods for stratifying a plurality of subjects, methods
for identifying an early indication, or methods for conducting a
clinical trials where the functional biomarker measured is dark
adaptation, the subject value can be based on the rod intercept
time, the rod-cone break time, the rod recovery slope, the time to
scotopic threshold, or a combination of the foregoing.
[0109] In the foregoing methods for selecting or identifying a
subject, methods for stratifying a plurality of subjects, methods
for identifying an early indication, or methods for conducting a
clinical trial the statin may be any statin approved for
administration to the subject or undergoing evaluation for approval
(such as in a clinical trial), including, but not limited to,
atorvastatin (LIPITOR.RTM.), cerivastatin, fluvastatin
(LESCOL.RTM.), lovastatin (MEVACOR.RTM., ALTOCOR.TM.), pitavastatin
(LIVALO.RTM.), pravastatin (PRAVACHOL.RTM., SELEKTINE.RTM.),
rosuvastatin (CRESTOR.RTM.) simvastatin (ZOCOR.RTM.), analogs
thereof, and combinations thereof.
[0110] In the foregoing methods for selecting or identifying a
subject, methods for stratifying a plurality of subjects, methods
for identifying an early indication, or methods for conducting a
clinical trial, the statin may be atorvastatin (LIPITOR.RTM.).
[0111] In the foregoing methods for selecting or identifying a
subject, methods for stratifying a plurality of subjects, methods
for identifying an early indication, or methods for conducting a
clinical trial where dark adaptation is measured any of the
following conditions may be used:
[0112] a 70% effective bleach and a 5.degree. or 12.degree.
eccentricity test location;
[0113] a 76% effective bleach and a 5.degree. or 12.degree.
eccentricity test location;
[0114] a 70% effective bleach and a 5.degree. eccentricity test
location;
[0115] a 70% effective bleach and a 12.degree. eccentricity test
location;
[0116] a 76% effective bleach and a 5.degree. eccentricity test
location; and
[0117] a 76% effective bleach and a 12.degree. eccentricity test
location.
[0118] In any of the foregoing conditions, the 5.degree. or
12.degree. eccentricity test location may be centered on the
inferior visual meridian.
[0119] In the foregoing methods for selecting or identifying a
subject, methods for stratifying a plurality of subjects, methods
for identifying an early indication, or methods for conducting a
clinical trial where the rod intercept time is determined, the rod
intercept criterion sensitivity level may be from 5.times.10.sup.-2
scotopic cd/m.sup.2 to 5.times.10.sup.-4 scotopic cd/m2. In any of
the foregoing embodiments where the rod intercept time is
determined, the rod intercept criterion sensitivity level may be
5.times.10.sup.-3 scotopic cd/m.sup.2.
[0120] Management of AMD Therapy
[0121] The disclosed functional biomarkers can also be used for
management of AMD patients who are candidates for or who are using
statin therapy. While statins are one of the most frequently
prescribed drugs, their use has typically been the purview of
cardiologists and internists attempting to lower cholesterol levels
as a means for reducing the risk of cardiovascular diseases such as
heart attacks and strokes. AMD is largely diagnosed and managed by
eye care physicians such as ophthalmologists and optometrists who
are in general not intimately familiar with administration of
statins, the detailed physiological response, or the associated
side effects. There is a need to provide tools for these eye care
physicians to enable easy, effective management of statin therapy
for AMD. The challenges faced by the physician include, for
example, the uncertainly of whether a particular patient will
respond or not, a long treatment duration (in some cases twelve
months or more) before definitive structural indications of
response are evident, and the risk of adverse side effects, some of
which can be serious. Consequently, some patients may be exposed to
prolonged risk before learning whether there is commensurate
benefit. Thus, the disclosed functional biomarkers can be used, for
example, to support treatment of AMD patients using statin therapy
by, for example, identifying patients more likely to respond,
providing an early indication of responders vs. non-responders, or
demonstrating a treatment benefit, e.g., within 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, or 12 months of initiation of treatment.
[0122] In some methods, one or more of the functional biomarkers
disclosed herein is measured at the initiation of therapy to
provide a subject value that indicates the likelihood of a
treatment effect or a baseline value to track treatment effect. In
some embodiments, an impaired subject value indicates the potential
for treatment response; for example, allowing the physician to
decide whether the patient should be treated using a statin
therapy. During or after administration of a statin treatment
(e.g., at one or more of 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 24,
and/or 36 weeks, or 30, 60, 90, 180, 270 and/or 360 days, or 1, 2,
3, and/or 4 quarters after initiation of the treatment), the one or
more functional biomarkers disclosed herein can be measured again
to provide a subsequent value, and the subsequent value compared to
the baseline value or an earlier subsequent value. In some
embodiments, an improvement from the baseline value indicates that
the therapy is effective or is likely to be effective for the
patient. In some embodiments, no change or a worsening from the
baseline value indicates that the therapy is ineffective or is
likely to be ineffective for the patient; in this case, the
treatment can, for example, be discontinued or the dose increased.
In some embodiments, for example in patients who are expected to
experience rapidly worsening disease based on medical history, no
change from the baseline value can indicate that the therapy is
effective or likely to be effective for the patient. In some
embodiments, the disclosed functional biomarkers can be used to
confirm a treatment benefit. Alternatively, these biomarkers can be
used to identify patients more likely to respond to statin therapy
or to provide an early indication of responders vs.
non-responders.
[0123] In some embodiments, when deciding whether to treat a
patient with statin therapy, those with an impaired functional
biomarker (e.g., delayed dark adaptation or a larger than normal
low luminance deficit) are more likely to respond to intervention,
simply because they have deficits that can be corrected. In other
embodiments, once treatment has started, improvement in a
functional biomarker (e.g., a shortening of dark adaptation time or
a lessening of low luminance deficit) is an early indicator of
treatment efficacy and consequently indicates those more likely to
have follow-on benefits such as disappearance of drusen or
improvement in visual acuity.
[0124] As previously noted, it would be advantageous to limit the
exposure to risks associated with statin therapy by identifying in
advance those patients most likely to respond and by having a quick
indication whether the treatment is having an effect after
initiation. The risks associated with statin therapy generally fall
into four categories (Golomb et al., 2008 Am J Cardiovasc Drugs
8(6):373-418):
[0125] Muscle Pain and Damage--The most common risk of statin
therapy is mild to severe muscle pain. Very rarely (in a few cases
per million), statin therapy is associated with rhabdomyolysis, a
life-threatening muscle damage that can result in severe muscle
pain, liver damage, kidney failure and even death.
[0126] Liver Damage--Statin therapy occasionally causes an increase
in the level of enzymes that signal liver inflammation.
[0127] Increased Blood Glucose--There is a small risk of increased
blood glucose that could lead to developing type 2 diabetes.
[0128] Neurological Side Effects--Some people have developed
reversible memory loss or confusion while taking statins.
[0129] The risks of statin therapy are greatest for females, being
age 65 or older, those having a smaller body frame, those having
kidney or liver disease, and those taking multiple medications to
lower cholesterol. In addition, numerous other drugs may interact
adversely with statins, including amiodarone, gemfibrozil, protease
inhibitors such as saquinavir and ritonavir, some antibiotics and
antifungal medications such as clarithromycin and itraconazole, and
some immunosuppressants such as cyclosporine.
[0130] Therefore, the following methods are provided in the present
disclosure.
[0131] The present disclosure provides a method for determining or
predicting efficacy of a treatment for AMD in a subject, wherein
the treatment comprises administration of a statin. The method
comprises the steps of: 1) optionally identifying the subject or
having the subject identified as having AMD; 2) measuring or having
measured one or more functional biomarkers in the subject; 3)
determining or having determined a baseline value from the one or
more measurements of step 2; 4) administering or continuing to
administer a statin treatment to the subject; 5) measuring or
having measured the one or more functional biomarkers in the
subject at one or more second or later time points; 6) determining
or having determined a corresponding subsequent value from the one
or more measurements of step 5; and 7) optionally comparing the
baseline value to the one or more corresponding subsequent values
or comparing a subsequent value to an earlier subsequent value. In
some embodiments where the treatment for AMD has the objective of
preventing or delaying progression of AMD in the subject (for
example, to prevent or delay atrophy of the RPE, to prevent or
delay atrophy of one or more photoreceptors, to prevent or delay
vision loss, and/or to prevent or delay progression from early AMD
to advanced AMD), an improvement or no change in a subsequent value
as compared to the baseline value (or a subsequent value as
compared to an earlier subsequent value) indicates that the
treatment is effective or likely to be effective in the subject. In
some embodiments where the treatment for AMD has the objective of
regression of AMD in the subject (for example, regression of
drusen, regression of PEDs, and/or improvement in visual acuity)),
a worsening or no change of a subsequent value as compared to the
baseline value (or a subsequent value as compared to an earlier
subsequent value) indicates that the treatment is ineffective or
likely to be ineffective in the subject.
[0132] Such method may further comprise making a treatment decision
based on the subject value and the baseline value (or the
subsequent value and an earlier subsequent value). Such treatment
decisions include: i) continuing the statin treatment without
change; ii) continuing the statin treatment with an increase or
decrease in the dose of the statin being administered (as compared
to the initial dose); iii) continuing statin therapy with a
different statin than initially administered (either at the same
equivalent dose, a higher equivalent dose, or a lower equivalent
dose); and iv) discontinuing statin treatment. In a specific
embodiment, the treatment decision comprises or further comprises
taking one of the following actions: i) continuing to treat the
subject with the statin treatment at the initial statin dose (as
compared to the initial statin dose) if the subsequent value is
improved as compared to the baseline value (or an earlier
subsequent value); ii) continuing to treat the subject with the
statin treatment at the initial statin dose, continuing to treat
the subject with the statin therapy at an increased or decreased
statin dose (as compared to the initial statin dose), or continuing
the statin therapy with a different statin if the subsequent value
shows a change of less than 10% as compared to the baseline value
(or an earlier subsequent value); or iii) discontinuing treating
the subject with the statin treatment if the subsequent value shows
a worsening of greater than or equal to 10% as compared to the
baseline value (or an earlier subsequent value).
[0133] The present disclosure provides a method for determining or
predicting efficacy of a treatment for AMD in a subject, wherein
the treatment comprises administration of a statin. The method
comprises the steps of: 1) optionally identifying the subject or
having the subject identified as having AMD; 2) measuring or having
measured dark adaptation in the subject; 3) determining or having
determined the rod intercept time from the dark adaptation
measurement to provide a baseline value; 4) administering or
continuing to administer a statin treatment to the subject; 5)
measuring or having measured dark adaptation in the subject at one
or more second or later time points; 6) determining or having
determined the rod intercept time from the dark adaptation
measurement to provide a subsequent value; and 7) optionally
comparing the baseline value to the one or more subsequent values
or comparing a subsequent value to an earlier subsequent value. In
some embodiments where the treatment for AMD has the objective of
preventing or delaying progression of AMD in the subject (for
example, to prevent or delay atrophy of the RPE, to prevent or
delay atrophy of one or more photoreceptors, to prevent or delay
vision loss, and/or to prevent or delay progression from early AMD
to advanced AMD), an improvement or no change in a subsequent value
as compared to the baseline value (or a subsequent value as
compared to an earlier subsequent value) indicates that the
treatment is effective or likely to be effective in the subject. In
some embodiments where the treatment for AMD has the objective of
regression of AMD in the subject (for example, regression of
drusen, regression of PEDs, and/or improvement in visual acuity), a
worsening or no change of a subsequent value as compared to the
baseline value (or a subsequent value as compared to an earlier
subsequent value) indicates that the treatment is ineffective or
likely to be ineffective in the subject.
[0134] Such method may further comprise making a treatment decision
based on the subject value and the baseline value (or the
subsequent value and an earlier subsequent value). Such treatment
decisions include: i) continuing the statin treatment without
change; ii) continuing the statin treatment with an increase or
decrease in the dose of the statin being administered (as compared
to the initial dose); iii) continuing statin therapy with a
different statin than initially administered (either at the same
equivalent dose, a higher equivalent dose, or a lower equivalent
dose); and iv) discontinuing statin treatment. In a particular
embodiment, when the rod intercept time at a subsequent value is
improved 180 seconds or more from the baseline value (or an earlier
subsequent value), the treatment decision is to continue with the
statin therapy without change or to decrease the dose of the
statin. In a particular embodiment, when the change in rod
intercept time at a subsequent value is improved or worsened less
than 180 seconds from the baseline value (or an earlier subsequent
value), the treatment decision is to continue with the statin
therapy without change, continue the statin therapy with a
different statin, continue the statin treatment with an increase in
the dose of the statin being administered, continue the statin
treatment with an increase in the dose of the statin being
administered to 80 mg of atorvastatin daily or a dose equivalent to
80 mg of atorvastatin daily, or continue the statin treatment with
an increase in the dose of the statin being administered to between
80 mg and 120 mg of atorvastatin daily or a dose equivalent to 80
mg to 120 mg of atorvastatin daily. In a particular embodiment,
when the change in rod intercept time at a subsequent value is
worsened 180 seconds or more from the baseline value (or an earlier
subsequent value), the treatment decision is to discontinue
treating the subject with the statin therapy.
[0135] The present disclosure provides a method for treating a
subject with a statin, wherein the subject is suffering from AMD,
the method comprising the steps of: 1) measuring or having measured
one or more functional biomarkers in the subject; 2) determining or
having determined a baseline value for the subject from the one or
more measurements of step 1; 3) administering or continuing to
administer a statin treatment to the subject at an initial statin
dose; 4) measuring or having measured the one or more functional
biomarkers in the subject at one or more second or later time
points; 5) determining or having determined a subsequent value for
the subject from the one or more measurements of step 4; and 6)
making a treatment decision based on the subsequent value and the
baseline value (or the subsequent value and an earlier subsequent
value). Such treatment decisions includes: i) continuing the statin
treatment without change; ii) continuing the statin treatment with
an increase or decrease in the dose of the statin being
administered (as compared to the initial dose); iii) continuing
statin therapy with a different statin than initially administered
(either at the same equivalent dose, a higher equivalent dose, or a
lower equivalent dose); and iv) discontinuing statin treatment.
[0136] In a specific embodiment, the treatment decision comprises
or further comprises taking one of the following actions: i)
continuing to treat the subject with the statin treatment at the
initial statin dose (as compared to the initial statin dose) if the
subsequent value is improved as compared to the baseline value (or
an earlier subsequent value); ii) continuing to treat the subject
with the statin treatment at the initial statin dose, continuing to
treat the subject with the statin therapy at an increased or
decreased statin dose (as compared to the initial statin dose), or
continuing the statin therapy with a different statin if the
subsequent value shows a change of less than 10% as compared to the
baseline value (or an earlier subsequent value); or iii)
discontinuing treating the subject with the statin treatment if the
subsequent value shows a worsening of greater than or equal to 10%
as compared to the baseline value (or an earlier subsequent
value).
[0137] In certain embodiments, the statin treatment is atorvastatin
and the initial dose is from 40 mg to 120 mg daily. In certain
embodiments, the statin therapy is cerivastatin, fluvastatin,
lovastatin, pitavastatin, rosuvastatin, or simvastatin and the
initial dose is from 40 mg dose equivalent to atorvastatin to 120
mg dose equivalent to atorvastatin daily. In certain embodiments,
the increased statin dose is 1.5-fold to 10-fold the initial statin
dose. In certain embodiments, the increased statin dose is 2-fold
the initial statin dose. In certain embodiments, the increased
statin dose is 80 mg of atorvastatin or a dose equivalent to 80 mg
of atorvastatin daily. In certain embodiments, the increased statin
dose is 80 mg to 120 mg of atorvastatin or a dose equivalent to 80
mg to 120 mg of atorvastatin daily.
[0138] The present disclosure provides a method for treating a
subject with a statin, wherein the subject is suffering from AMD,
the method comprising the steps of: 1) measuring or having measured
dark adaptation in the subject; 2) determining or having determined
a rod intercept time from the dark adaptation measurement to
provide a baseline value; 3) administering or continuing to
administer a statin treatment to the subject at an initial statin
dose; 4) measuring or having measured dark adaptation in the
subject at one or more second or later time points; 5) determining
or having determined a rod intercept time from the dark adaptation
measurement to provide a subsequent value; and 6) making a
treatment decision based on the subsequent value and the baseline
value (or the subsequent value and an earlier subsequent value).
Such treatment decisions includes: i) continuing the statin
treatment without change; ii) continuing the statin treatment with
an increase or decrease in the dose of the statin being
administered (as compared to the initial dose); iii) continuing
statin therapy with a different statin than initially administered
(either at the same equivalent dose, a higher equivalent dose, or a
lower equivalent dose); and iv) discontinuing statin treatment.
[0139] In a specific embodiment, the treatment decision comprises
or further comprises taking one of the following actions: i) when
the rod intercept time at a subsequent value is improved 180
seconds or more from the baseline value (or an earlier subsequent
value), the treatment decision is to continue with the statin
therapy without change or continue with the statin therapy at a
decreased dose (as compared to the initial dose); ii) when the rod
intercept time at a subsequent value is improved or worsened less
than 180 seconds from the baseline value (or an earlier subsequent
value), the treatment decision is to continue with the statin
therapy without change, continue the statin therapy with a
different statin, continue the statin treatment with an increase or
decrease in the dose of the statin being administered (as compared
to the initial dose), continue the statin treatment with an
increase in the dose of the statin being administered to 80 mg of
atorvastatin daily or a dose equivalent to 80 mg of atorvastatin
daily, or continue the statin treatment with an increase in the
dose of the statin being administered to between 80 mg and 120 mg
of atorvastatin daily or a dose equivalent to 80 mg to 120 mg of
atorvastatin daily; or iii) when in rod intercept time at a
subsequent value is worsened greater than 180 seconds from the
baseline value (or an earlier subsequent value), the treatment
decision is to discontinue treating the subject with the statin
therapy.
[0140] In certain embodiments, the statin treatment is atorvastatin
and the initial dose is from 40 mg to 120 mg daily. In certain
embodiments, the statin therapy is cerivastatin, fluvastatin,
lovastatin, pitavastatin, rosuvastatin, or simvastatin and the
initial dose is from 40 mg dose equivalent to atorvastatin to 120
mg dose equivalent to atorvastatin daily. In certain embodiments,
the increased statin dose is 1.5-fold to 10-fold the initial statin
dose. In certain embodiments, the increased statin dose is 2-fold
the initial statin dose. In certain embodiments, the increased
statin dose is 80 mg of atorvastatin or a dose equivalent to 80 mg
of atorvastatin daily. In certain embodiments, the increased statin
dose is 80 mg to 120 mg of atorvastatin or a dose equivalent to 80
mg to 120 mg of atorvastatin daily.
[0141] The present disclosure provides a method for treating a
subject with a statin, wherein the subject is suffering from AMD,
the method comprising the steps of: 1) measuring or having measured
dark adaptation in the subject; 2) determining or having determined
a rod intercept time from the dark adaptation measurement to
provide a baseline value; 3) administering or continuing to
administer a statin treatment to the subject at an initial statin
dose; 4) measuring or having measured dark adaptation in the
subject at one or more second or later time points; 5) determining
or having determined a rod intercept time from the dark adaptation
measurement to provide a subsequent value; and 6) continuing to
treat the subject with the statin treatment at the initial statin
dose or at a decreased statin dose if the rod intercept time is
improved 180 seconds or more from the baseline value (or an earlier
subsequent value). In certain embodiments, the statin treatment is
atorvastatin and the initial statin dose is from 40 mg to 120 mg
daily. In certain embodiments, the statin therapy is cerivastatin,
fluvastatin, lovastatin, pitavastatin, rosuvastatin, or simvastatin
and the initial statin dose is from 40 mg dose equivalent to
atorvastatin to 120 mg dose equivalent to atorvastatin daily.
[0142] In certain embodiments, the statin treatment is atorvastatin
and the initial dose is from 40 mg to 120 mg daily. In certain
embodiments, the statin therapy is cerivastatin, fluvastatin,
lovastatin, pitavastatin, rosuvastatin, or simvastatin and the
initial dose is from 40 mg dose equivalent to atorvastatin to 120
mg dose equivalent to atorvastatin daily. In certain embodiments,
the increased statin dose is 1.5-fold to 10-fold the initial statin
dose. In certain embodiments, the increased statin dose is 2-fold
the initial statin dose. In certain embodiments, the increased
statin dose is 80 mg of atorvastatin or a dose equivalent to 80 mg
of atorvastatin daily. In certain embodiments, the increased statin
dose is 80 mg to 120 mg of atorvastatin or a dose equivalent to 80
mg to 120 mg of atorvastatin daily.
[0143] The present disclosure provides a method for treating a
subject with a statin, wherein the subject is suffering from AMD,
the method comprising the steps of: 1) measuring or having measured
dark adaptation in the subject; 2) determining or having determined
a rod intercept time from the dark adaptation measurement to
provide a baseline value; 3) administering or continuing to
administer a statin treatment to the subject at an initial statin
dose; 4) measuring or having measured dark adaptation in the
subject at one or more second or later time points; 5) determining
or having determined a rod intercept time from the dark adaptation
measurement to provide a subsequent value; and 6) continuing to
treat the subject with the statin treatment at an initial statin
dose, continuing to treat the subject with the statin therapy at an
increased statin dose (as compared to the initial statin dose), or
continuing the statin therapy with a different statin if the rod
intercept time is improved or worsened less than 180 seconds from
the baseline value (or an earlier subsequent value). In certain
embodiments, the increased statin dose is 1.5-fold to 10-fold the
initial statin dose. In certain embodiments, the increased statin
dose is 2-fold the initial statin dose. In certain embodiments, the
increased statin dose is 80 mg of atorvastatin or a dose equivalent
to 80 mg of atorvastatin daily. In certain embodiments, the
increased statin dose is 80 mg to 120 mg of atorvastatin or a dose
equivalent to 80 mg to 120 mg of atorvastatin daily.
[0144] In certain embodiments, the statin treatment is atorvastatin
and the initial dose is from 40 mg to 120 mg daily. In certain
embodiments, the statin therapy is cerivastatin, fluvastatin,
lovastatin, pitavastatin, rosuvastatin, or simvastatin and the
initial dose is from 40 mg dose equivalent to atorvastatin to 120
mg dose equivalent to atorvastatin daily. In certain embodiments,
the increased statin dose is 1.5-fold to 10-fold the initial statin
dose. In certain embodiments, the increased statin dose is 2-fold
the initial statin dose. In certain embodiments, the increased
statin dose is 80 mg of atorvastatin or a dose equivalent to 80 mg
of atorvastatin daily. In certain embodiments, the increased statin
dose is 80 mg to 120 mg of atorvastatin or a dose equivalent to 80
mg to 120 mg of atorvastatin daily.
[0145] The present disclosure provides a method for treating a
subject with a statin, wherein the subject is suffering from AMD,
the method comprising the steps of: 1) measuring or having measured
dark adaptation in the subject; 2) determining or having determined
a rod intercept time from the dark adaptation measurement to
provide a baseline value; 3) administering or continuing to
administer a statin treatment to the subject at an initial statin
dose; 4) measuring or having measured dark adaptation in the
subject at one or more second or later time points; 5) determining
or having determined a rod intercept time from the dark adaptation
measurement to provide a subsequent value; and 6) discontinuing
treating the subject with the statin treatment if the rod intercept
time is worsened 180 seconds or more from the baseline value (or an
earlier subsequent value).
[0146] In certain embodiments, the statin treatment is atorvastatin
and the initial dose is from 40 mg to 120 mg daily. In certain
embodiments, the statin therapy is cerivastatin, fluvastatin,
lovastatin, pitavastatin, rosuvastatin, or simvastatin and the
initial dose is from 40 mg dose equivalent to atorvastatin to 120
mg dose equivalent to atorvastatin daily. In certain embodiments,
the increased statin dose is 1.5-fold to 10-fold the initial statin
dose. In certain embodiments, the increased statin dose is 2-fold
the initial statin dose. In certain embodiments, the increased
statin dose is 80 mg of atorvastatin or a dose equivalent to 80 mg
of atorvastatin daily. In certain embodiments, the increased statin
dose is 80 mg to 120 mg of atorvastatin or a dose equivalent to 80
mg to 120 mg of atorvastatin daily.
[0147] The present disclosure also provides a method of selecting a
subject for treatment with a statin therapy, wherein the subject is
suffering from AMD, the method comprising the steps of: 1)
measuring or having measured one or more functional biomarkers in
the subject; 2) determining or having determined a subject value
for the subject from the one or more measurements of step 1; 3)
comparing the subject value to a corresponding reference range; and
4) selecting the subject for treatment with the statin therapy if
the subject value falls within the reference range or not selecting
the subject for treatment with the statin therapy if the subject
value falls outside the reference range. In certain embodiments,
the statin therapy is atorvastatin and the dose is from 40 mg to
120 mg daily. In certain embodiments, the statin therapy is
cerivastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin,
or simvastatin and the dose is a dose equivalent to 40 mg to 120 mg
of atorvastatin daily.
[0148] The present disclosure also provides a method of selecting a
subject for treatment with a statin therapy, wherein the subject is
suffering from AMD, the method comprising the steps of: 1)
measuring or having measured dark adaptation in the subject; 2)
determining or having determined the rod intercept time from the
dark adaptation measurement to provide a subject value; 3)
comparing the subject value to a corresponding reference range; and
4) selecting the subject for treatment with the statin therapy if
the subject value falls within the reference range or not selecting
the subject for treatment with the statin therapy if the subject
value falls outside the reference range. In certain embodiments,
the statin therapy is atorvastatin and the dose is from 40 mg to
120 mg daily. In certain embodiments, the statin therapy is
cerivastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin,
or simvastatin and the dose is a dose equivalent to 40 mg to 120 mg
of atorvastatin daily.
[0149] I In any of the foregoing methods of determining or
predicting efficacy, methods of treatment, or methods of selection,
the statin may be any statin approved for administration to the
subject or undergoing evaluation for approval (such as in a
clinical trial), including, but not limited to, atorvastatin
(LIPITOR.RTM.), cerivastatin, fluvastatin (LESCOL.RTM.), lovastatin
(MEVACOR.RTM., ALTOCOR.TM.), pitavastatin (LIVALO.RTM.),
pravastatin (PRAVACHOL.RTM., SELEKTINE.RTM.), rosuvastatin
(CRESTOR.RTM.) simvastatin (ZOCOR.RTM.), analogs thereof, and
combinations thereof.
[0150] In any of the foregoing methods of determining or predicting
efficacy, methods of treatment, or methods of selection where dark
adaptation is measured any of the following conditions may be
used:
[0151] a 70% effective bleach and a 5.sup.0 or 12.degree.
eccentricity test location;
[0152] a 76% effective bleach and a 5.degree. or 12.degree.
eccentricity test location;
[0153] a 70% effective bleach and a 5.degree. eccentricity test
location;
[0154] a 70% effective bleach and a 12.degree. eccentricity test
location;
[0155] a 76% effective bleach and a 5.degree. eccentricity test
location; and
[0156] a 76% effective bleach and a 12.degree. eccentricity test
location.
[0157] In any of the foregoing conditions, the 5'' or 12.degree.
eccentricity test location may be centered on the inferior visual
meridian.
[0158] In any of the foregoing methods of determining or predicting
efficacy, methods of treatment, or methods of selection where the
rod intercept time is determined, the rod intercept criterion
sensitivity level may be from 5.times.10.sup.-2 scotopic cd/m.sup.2
to 5.times.10.sup.-4 scotopic cd/m.sup.2. In any of the foregoing
embodiments where the rod intercept time is determined, the rod
intercept criterion sensitivity level may be 5.times.10.sup.-3
scotopic cd/m.sup.2.
[0159] In any of the foregoing methods of determining or predicting
efficacy, methods of treatment, or methods of selection, the
methods of treatment may have the objective of regressing drusen
(e.g., soft drusen), regressing PEDs, preventing or delaying
atrophy of the RPE, preventing or delaying atrophy of one or more
photoreceptors, preventing or delaying vision loss, improving
vision (e.g., visual acuity), and/or preventing or delaying
progression from early AMD to advanced AMD (e.g., geographic
atrophy or choroidal neovascularization).
[0160] In any of the foregoing methods of determining or predicting
efficacy, methods of treatment, or methods of selection, the
subjects may have soft drusen. In any of the foregoing methods of
treatment, the subjects may be determined after clinical assessment
to have early AMD. In any of the foregoing methods of treatment,
the subjects may be determined after clinical assessment to have
intermediate AMD. In any of the foregoing methods of treatment, the
subjects may have SDDs.
[0161] In any of the foregoing methods of determining or predicting
efficacy, methods of treatment, or methods of selection, the
baseline value may be determined prior to the initiation of statin
treatment or concurrently with the initiation of statin treatment.
In any of the foregoing methods of treatment or methods of
selection, a subsequent value may be taken 1 month or greater from
the baseline value or an earlier subsequent value. In any of the
foregoing methods of treatment or methods of selection, a
subsequent value may be taken 3 months or greater from the baseline
value or an earlier subsequent value. In any of the foregoing
methods of treatment or methods of selection, a subsequent value
may be taken 6 months or greater from the baseline value or an
earlier subsequent value. In any of the foregoing methods of
treatment or methods of selection, a subsequent value may be taken
12 months or greater from the baseline value or an earlier
subsequent value.
[0162] Statins
[0163] The methods described herein include administration of
high-dose statins, for example as described in international patent
application WO 2017/066529. Statins (or HMG-CoA reductase
inhibitors) are a class of cholesterol lowering drugs that are
similar in structure to HMG-CoA, shown below:
##STR00001##
Statins inhibit the enzyme HMG-CoA reductase by competitively
binding to HMG-CoA reductase in the HMG-CoA active site. Any statin
may be used in connection with the methods described herein.
Non-limiting examples of statins include: atorvastatin
(LIPITOR.RTM.), cerivastatin, fluvastatin (LESCOL.RTM.), lovastatin
(MEVACOR.RTM., ALTOCOR.TM.), pitavastatin (LIVALO.RTM.),
pravastatin (PRAVACHOL.RTM., SELEKTINE.RTM.), rosuvastatin
(CRESTOR.RTM.) simvastatin (ZOCOR.RTM.), analogs thereof, and
combinations thereof. In some embodiments, the statin used in a
method described herein is atorvastatin.
[0164] Statins can be either lipophilic or hydrophilic. Lipophilic
statins include, for example, atorvastatin, lovastatin, and
simvastatin. Hydrophilic statins include, for example, fluvastatin,
rosuvastatin, and pravastatin. In some embodiments, the statin used
in a method described herein is lipophilic (e.g.,
atorvastatin).
[0165] As used herein the term "high-dose" refers to any dose that
exceeds the defined daily dose (DDD) according to the World Health
Organization (WHO). The 2015 ATC/DDD Index indicates the DDD as 20
mg for atorvastatin, 0.2 mg for cerivastatin, 60 mg for
fluvastatin, 45 mg for lovastatin, 2 mg for pitavastatin, 30 mg for
pravastatin, 10 mg for rosuvastatin, and 30 mg for simvastatin
(see, e.g., whocc.no/atc_ddd_index/). For example, in embodiments
where the statin used in a method described herein is atorvastatin
(having a DDD of 20 mg), a high-dose of atorvastatin can be at
least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at
least 80 mg, at least 90 mg, at least 100 mg, at least 120 mg, at
least 140 mg, or at least 160 mg. In some embodiments, the dose
used is at least 80 mg for atorvastatin (e.g., 80-100, 80-120,
80-140, or 80-160 mg).
[0166] In other embodiments, where the statin used in a method
described herein is a statin other than atorvastatin, a dose
equivalent of high-dose atorvastatin can be used. Equivalent doses
of other statins can be easily determined by a skilled person. For
example, based on the DDD of the statins, an equivalent dose of 80
mg atorvastatin could be 0.8 mg for cerivastatin, 240 mg for
fluvastatin, 180 mg for lovastatin, 8 mg for pitavastatin, 120 mg
for pravastatin, 40 mg for rosuvastatin, and 120 mg for
simvastatin. In some embodiments, the dose used is at least 0.8 mg
for cerivastatin (e.g., 0.8-1.0, 0.8-1.2, 0.8-1.4, or 0.8-1.6 mg);
at least 80 mg for fluvastatin (e.g., 80-100, 80-120, 80-140, or
80-160 mg); at least 80 mg for lovastatin (e.g., 80-100, 80-120,
80-140, or 80-160 mg); at least 4 mg for pitavastatin (e.g., 4-6,
4-8, or 4-10 mg); at least 40 mg for pravastatin (e.g., 40-50,
40-60, 40-70, or 40-80 mg); at least 40 mg for rosuvastatin (e.g.,
40-50, 40-60, 40-70, or 40-80 mg); and at least 80 mg for
simvastatin (e.g., 80-100, 80-120, 80-140, or 80-160 mg).
[0167] Also provided herein are methods that include administration
of maintenance-dose statins. For example, following effective
treatment of AMD, the amount of statin administered can be reduced
from a high-dose statin to a maintenance-dose statin. As used
herein a "maintenance dose" is lower than the high-dose and
indicates a dose of statin that is about equal to the DDD according
to the WHO of a statin. For example, a maintenance dose of
atorvastatin (having a DDD of 20 mg) can be about 15 mg, about 20
mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45
mg, about 50 mg, about 55 mg, or about 60 mg. In some embodiments,
a maintenance-dose statin is about 60 mg atorvastatin. In some
embodiments, a maintenance-dose statin is about 40 mg
atorvastatin.
[0168] In other embodiments, where the statin used in a method
described herein is a statin other than atorvastatin, a dose
equivalent of maintenance-dose atorvastatin can be used. Equivalent
doses of other statins can be easily determined by a skilled
person. For example, based on the DDD of the statins, an equivalent
maintenance-dose of 40 mg atorvastatin could be 0.4 mg for
cerivastatin, 120 mg for fluvastatin, 90 mg for lovastatin, 4 mg
for pitavastatin, 60 mg for pravastatin, 20 mg for rosuvastatin,
and 60 mg for simvastatin.
[0169] In some embodiments, the statin is administered
systemically, e.g., orally or parenterally. If not otherwise
specified herein, a recited dose of a statin will be understood to
be a daily dose.
1. EXAMPLES
[0170] The invention is further described in the following
examples, which do not limit the scope of the invention described
in the claims.
Example 1--Improvement in Contrast Sensitivity After Initiation of
Statin Treatment
[0171] An adult female patient having intermediate AMD was treated
with oral atorvastatin at doses increasing to 80 mg per day over
six months. The patient was asked to report any perceived changes
in visual function during the course of the treatment. The patient,
an artist, self-reported improvement in contrast sensitivity after
initiation of the treatment. This self-reported improvement in
contrast sensitivity occurred well in advance of eventual
resolution of the drusen associated with her AMD. No objective
testing was done to document the improvement in contrast
sensitivity. However, as an artist this patient was keenly aware of
her visual functions, so her self-reported improvement in contrast
sensitivity had substantial credence.
Example 2--Improvement in Dark Adaptation Precedes Drusen
Resolution After Statin Treatment
[0172] An adult male patient having intermediate AMD was treated
with oral atorvastatin for 23 months according to the following
schedule.
TABLE-US-00001 Month 1 10 mg per day Month 2 20 mg per day Month 3
40 mg per day Months 4 through 7 60 mg per day Months 8 through 23
80 mg per day
[0173] The patient was asked to report any perceived changes in
visual function during the course of the treatment. The patient, a
professional photographer, self-reported improvement in dark
adaptation at month 7 of treatment. The self-reported improvement
was confirmed at months 15 and 22 of treatment. In addition, at
month 15 of treatment an ophthalmic examination of the patient
indicated substantially complete resolution of the drusen
associated with his AMD. The resolution of the drusen was confirmed
by fundus photography and optical coherence tomography (OCT)
imaging. The self-reported improvement in dark adaptation (first
reported at month 7) occurred well in advance of clinically evident
reduction in drusen load (first determined at month 15). No
objective testing was done to document the improvement in dark
adaptation. However, as a professional photographer, this patient
was keenly aware of his visual function--in particular his ability
to make transitions from light to darkness when entering his
photographic dark room to develop film so his self-reported
improvement in dark adaptation had substantial credence.
Example 3--Changes in Dark Adaptation Parameters Are Indicative of
Clinical Outcome in AMD Patients Undergoing Statin Treatment
[0174] Dark adaptation data, and optionally other visual function
data, was collected for a case series of seven AMD patients being
treated with statin therapy. Table 1 shows demographic information
for the seven patients and details regarding their statin
therapy.
TABLE-US-00002 TABLE 1 Patient Sex Date of Birth Statin Dose
(mg/day) Start Date 1 M Feb. 11, 1938 atorvastatin 20 to 80 July
2013 2 F Apr. 8, 1946 atorvastatin 80 January 2013 3 M Jan. 20,
1939 atorvastatin 80 October 2016 4 F Feb. 11, 1947 atorvastatin 80
May 2018 5 F Apr. 28, 1943 atorvastatin 80 January 2014*
atorvastatin 20 February 2016 pravastatin 20 April 2018 6 F May 10,
1952 atorvastatin 80 November 2017 7 M Apr. 11, 1942 atorvastatin
10 to 20 April 2016 *Patient 5 suspended statin therapy between
January 2015 and February 2016
[0175] Drusen, along with other structural features such as PEDs
and pigmentary changes, have been used by clinicians as one
indicator of AMD and its progression or regression. The presence of
drusen per se does not directly interfere with dark adaptation or
other visual functions in a significant way. However, as previously
explained, the BlinD and BlamD that form on BM as precursors to
development of drusen can act as a transport barrier between the
RPE and choroid, impeding the supply of oxygen and nutrients coming
from the choroid to the RPE and the removal of waste products going
the opposite direction. This transport barrier can disrupt the
visual cycle and thereby have a dramatic negative affect on dark
adaptation parameters, including the rod intercept time (also
referred to as RI time or RI value). Since lipids are a major
component of Bind) and BlamD, therapies such as the administration
of statins drugs that have the ability to affect lipid accumulation
and/or distribution may be able to decrease and/or regress drusen
and the underlying BlinD and. BlamD accumulation. Since BlinD and
BlamD can impact dark adaptation parameters, including the RI time,
dark adaptation parameters, including, but not limited to, the RI
time, have the ability to serve as functional biomarkers for AMD
and its progression or regression. Furthermore, the use of dark
adaptation parameters, including, but not limited to the RI time,
is also linked to the mechanisms of action of statin therapy.
Consequently, the use of a dark adaptation parameter, such as, but
not limited to, the RI time, as a functional biomarker for AMD in
patients undergoing statin therapy relics, at least in part, on
different physiological processes and manifestations than other
biomarkers for AMD, such as but not limited to, drusen, PEDs, and
pigmentary changes.
[0176] Table 2 provides detailed information regarding patients 1
to 7, including the baseline diagnosis (diagnosis made when
starting statin therapy), ending diagnosis (the diagnosis made on
the date of the last referenced evaluation), the results of
evaluations performed on each patient, and whether the patient
responded to statin therapy. The dark adaptation data in this
Example is the rod intercept time (or RI time) reported in minutes.
In this Example, the dark adaptation data was collected using the
AdaptDx.RTM. Dark Adaptometer (MacuLogix, Middletown, Pa.) running
its standard Extended Test protocol. The Extended Test protocol
employs a 76% effective bleach and a test location of 5.degree.
eccentricity on the inferior visual meridian. Data is automatically
analyzed by the AdaptDx Dark Adaptometer to provide an RI time
based on recovery to a criterion sensitivity level of
5.times.10.sup.-3 scotopic cd/m.sup.2. A value of >20 minutes
indicates that an RI time could not be determined for that patient
at the expiration of 20 minutes of testing. The visual acuity data
was collected using a standard Snellen or ETDRS eye chart with the
results presented using the standard 20/20 vision scale. Drusen
resolution was determined by evaluation of fundus and OCT imaging
by qualified clinicians experienced in AMD evaluation. Fundus and
OCT imaging data was collected using the Heidelberg Engineering
Spectralis.RTM. SD-OCT (Heidelberg, Germany) or the Karl Zeiss
Meditec Cirrus.RTM. HD-OCT (Jena, Germany), in both cases running
standard protocols with automated data analysis performed by the
instruments.
TABLE-US-00003 TABLE 2 Date Month OD OS Responder Patient #1 July
2013 0 Intermediate AMD Intermediate AMD July 2013 0 VA 20/25 VA
20/32 July 2015 24 RI > 20 RI = 17.13 June 2018 59 VA 20/25 VA
20/25 June 2018 59 No indication of drusen resolution OU July 2018
60 RI > 20 RI > 20 July 2018 60 Intermediate AMD Intermediate
AMD No Patient #2 January 2013 0 Intermediate AMD Intermediate AMD
January 2015 24 RI = 18.72 RI = 9.88 December 2015 35 Substantially
complete drusen resolution December 2015 35 Decrease in retina
volume of 0.26 mm.sup.3 August 2016 43 Substantially complete
drusen resolution August 20